Chemokine receptor binding heterocyclic compounds with enhanced efficacy

ABSTRACT

The invention relates to heterocyclic compounds consisting of a core nitrogen atom surrounded by three pendant groups, wherein two of the three pendant groups are preferably benzimidazolyl methyl and tetrahydroquinolyl, and the third pendant group contains N and optionally contains additional rings. The compounds bind to chemokine receptors, including CXCR4 and CCR5, and demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/457,034 filed 6Jun. 2003, which is a continuation-in-part of U.S. Ser. No.10/446,170filed 23 May 2003 which is a continuation-in-part of U.S. Ser. No.10/329,329 filed 23 Dec. 2002 which claims benefit of U.S. provisionalapplication Ser. No. 60/342,716 filed 21 Dec. 2001 and to U.S.provisional application Ser. No. 60/350,822 filed 17 Jan. 2002. Thecontents of these applications are incorporated herein by reference.

TECHNICAL FIELD

This invention generally relates to novel compounds, pharmaceuticalcompositions and their use. This invention more specifically relates tonovel heterocyclic compounds that bind to chemokine receptors, includingCXCR4 and CCR5, and demonstrate protective effects against infection oftarget cells by a human immunodeficiency virus (HIV).

BACKGROUND OF THE INVENTION

Approximately 40 human chemokines have been described, that function, atleast in part, by modulating a complex and overlapping set of biologicalactivities important for the movement of lymphoid cells andextravasation and tissue infiltration of leukocytes in response toinciting agents (See, for example: P. Ponath, Exp. Opin. Invest. Drugs,7:1-18, 1998). These chemotactic cytokines, or chemokines, constitute afamily of proteins, approximately 8-10 kDa in size. Chemokines appear toshare a common structural motif, that consists of 4 conserved cysteinesinvolved in maintaining tertiary structure. There are two majorsubfamilies of chemokines: the “CC” or β-chemokines and the “CXC” orα-chemokines. The receptors of these chemokines are classified basedupon the chemokine that constitutes the receptor's natural ligand.Receptors of the β-chemokines are designated “CCR”; while those of theα-chemokines are designated “CXCR.”

Chemokines are considered to be principal mediators in the initiationand maintenance of inflammation (see Chemokines in Disease published byHumana Press (1999), Edited by C. Herbert; Murdoch et al. Blood 95,3032-3043 (2000)). More specifically, chemokines have been found to playan important role in the regulation of endothelial cell function,including proliferation, migration and differentiation duringangiogenesis and re-endothelialization after injury (Gupta et al., J.Biolog. Chem., 7:4282-4287, 1998). Two specific chemokines have beenimplicated in the etiology of infection by human immunodeficiency virus(HIV).

In most instances, HIV initially binds via its gp120 envelope protein tothe CD4 receptor of the target cell. A conformational change appears totake place in the gp120 which results in its subsequent binding to achemokine receptor, such as CCR-5 (Wyatt et al., Science, 280:1884-1888(1998)). HIV-1 isolates arising subsequently in the infection bind tothe CXCR-4 chemokine receptor. In view of the fact that the felineimmunodeficiency virus, another related retrovirus, binds to a chemokinereceptor without needing to bind first to the CD4 receptor, suggeststhat chemokine receptors may be the primordial obligate receptors forimmunodeficiency retroviruses.

Following the initial binding by HIV to CD4, virus-cell fusion results,which is mediated by members of the chemokine receptor family, withdifferent members serving as fusion cofactors for macrophage-tropic(M-tropic) and T cell line-tropic (T-tropic) isolates of HIV-1 (Carrollet al., Science, 276: 273-276 1997; Feng et al. Science 272, 872-877(1996); Bleul et al. Nature 382, 829-833 (1996); Oberlin et al. Nature382, 833-835 (1996); Cocchi et al. Science 270, 1811-1815 (1995); Dragicet al. Nature 381, 667-673 (1996); Deng et al. Nature 381, 661-666(1996); Alkhatib et al. Science 272, 1955-1958, 1996). During the courseof infection within a patient, it appears that a majority of HIVparticles shift from the M-tropic to the more aggressive pathogenicT-tropic viral phenotype (Miedema et al., Immune. Rev., 140:35 (1994);Blaak et al. Proc. Natl. Acad. Sci. 97, 1269-1274 (2000); Simmonds etal. J. Virol. 70, 8355-8360 (1996); Tersmette et al. J. Virol. 62,2026-2032, 1988); Connor, R. I., Ho, D. D. J. Virol. 68, 4400-4408(1994); Schuitemaker et al. J. Virol. 66, 1354-1360 (1992)). TheM-tropic viral phenotype correlates with the virus's ability to enterthe cell following binding of the CCR-5 receptor, while the T-tropicviral phenotype correlates with viral entry into the cell followingbinding and membrane fusion with the CXCR-4 receptor. Clinicallyobservations suggest that patients who possess genetic mutations in theCCR-5 or CXCR-4 appear resistant or less susceptible to HIV infection(Liu et al. Cell 86, 367-377 (1996); Samson et al. Nature 382, 722-725(1996); Michael et al. Nature Med. 3, 338-340 (1997); Michael et al. J.Virol. 72, 6040-6047 (1998); Obrien et al. Lancet 349, 1219 (1997);Zhang et al. AIDS Res. Hum. Retroviruses 13, 1357-1366 (1997); Rana etal. J. Virol. 71, 3219-3227 (1997); Theodorou et al. Lancet 349,1219-1220 (1997). Despite the number of chemokine receptors which havebeen reported to HIV mediate entry into cells, CCR5 and CXCR4 appear tobe the only physiologically relevant coreceptors used by a wide varietyof primary clinical HIV-1 strains (Zhang et al. J. Virol. 72, 9307-9312(1998); Zhang et al. J. Virol. 73, 3443-3448 (1999); Simmonds et al. J.Virol. 72, 8453-8457 (1988)). Fusion and entry of T-tropic viruses thatuse CXCR4 are inhibited by the natural CXC-chemokine stromalcell-derived factor-1, whereas fusion and entry of M-tropic viruses thatuse CCR5 are inhibited by the natural CC-chemokines namely, Regulated onActivation Normal T-cell Expressed and Secreted (RANTES) and MacrophageInflammatory proteins (MIP-1 alpha and beta).

However, the binding of chemokine receptors to their natural ligandsappears to serve a more evolutionary and central role than only asmediators of HIV infection. The binding of the natural ligand,pre-B-cell growth-stimulating factor/stromal cell derived factor(PBSF/SDF-1) to the CXCR4 chemokine receptor provides an importantsignaling mechanism: CXCR4 or SDF-1 knock-out mice exhibit cerebellar,cardiac and gastrointestinal tract abnormalities and die in utero (Zouet al., Nature, 393:591-594 (1998); Tachibana et al., Nature,393:591-594 (1998); Nagasawa et al. Nature 382, 635-638 (1996)).CXCR4-deficient mice also display hematopoietic defects (Nagasawa et al.Nature 382, 635-638 (1996)); the migration of CXCR4 expressingleukocytes and hematopoietic progenitors to SDF-1 appears to beimportant for maintaining B-cell lineage and localization of CD34⁺progenitor cells in bone marrow (Bleul et al. J. Exp. Med. 187, 753-762(1998); Viardot et al. Ann. Hematol. 77, 195-197 (1998); Auiti et al. J.Exp. Med. 185, 111-120 (1997); Peled et al. Science 283, 845-848 (1999);Qing et al. Immunity 10, 463-471 (1999); Lataillade et al. Blood 95,756-768 (1999); Ishii et al. J. Immunol. 163, 3612-3620 (1999); Maekawaet al. Internal Medicine 39, 90-100 (2000); Fedyk et al. J. LeukocyteBiol. 66, 667-673 (1999); Peled et al. Blood 95, 3289-3296 (2000)).

The signal provided by SDF-1 on binding to CXCR4 may also play animportant role in tumor cell proliferation and regulation ofangiogenesis associated with tumor growth (See “Chemokines and Cancer”published by Humana Press (1999); Edited by B. J. Rollins; Arenburg etal. J. Leukocyte Biol. 62, 554-562 (1997); Moore et al. J. Invest. Med.46, 113-120 (1998); Moore et al. Trends cardiovasc. Med. 8, 51-58(1998); Seghal et al. J. Surg. Oncol. 69, 99-104 (1998)); the knownangiogenic growth factors VEG-F and bFGF, up-regulate levels of CXCR4 inendothelial cells, and SDF-1 can induce neovascularization in vivo(Salcedo et al. Am. J. Pathol. 154, 1125-1135 (1999)); Leukemia cellsthat express CXCR4 migrate and adhere to lymph nodes and bone marrowstromal cells that express SDF-1 (Burger et al. Blood 94, 3658-3667(1999); Arai et al. Eur. J. Haematol. 64, 323-332 (2000); Bradstock etal. Leukemia 14, 882-888 (2000)).

The binding of SDF-1 to CXCR4 has also been implicated in thepathogenesis of atherosclerosis (Abi-Younes et al. Circ. Res. 86,131-138 (2000)), renal allograft rejection (Eitner et al.Transplantation 66, 1551-1557 (1998)), asthma and allergic airwayinflammation (Yssel et al. Clinical and Experimental Allergy 28, 104-109(1998); J. Immunol. 164, 5935-5943 (2000); Gonzalo et al. J. Immunol.165, 499-508 (2000)), Alzheimer's disease (Xia et al. J. Neurovirology5, 32-41 (1999)) and Arthritis (Nanki et al. J. Immunol. 164, 5010-5014(2000)).

In attempting to better understand the relationship between chemokinesand their receptors, recent experiments to block the fusion, entry andreplication of HIV via the CXCR4 chemokine receptor were carried outthrough the use of monoclonal antibodies or small molecules that appearto suggest a useful therapeutic strategy (Schols et al., J. Exp. Med.186:1383-1388 (1997); Schols et al., Antiviral Research 35:147-156(1997); Bridger et al. J. Med. Chem. 42, 3971-3981 (1999); Bridger etal. “Bicyclam Derivatives as HIV Inhibitors” in Advances in AntiviralDrug Design Volume 3, p 161-229; Published by JAI press (1999); Editedby E. De Clercq). Small molecules, such as bicyclams, appear tospecifically bind to CXCR4 and not CCR5 (Donzella et al., NatureMedicine, 4:72-77 (1998)). These experiments demonstrated interferencewith HIV entry and membrane fusion into the target cell in vitro. Morerecently, bicyclams were also shown to inhibit fusion and replication ofFeline Immunodeficiency Virus (FIV) that uses CXCR4 for entry (Egberinket al. J. Virol. 73, 6346-6352 (1999)).

Additional experiments have shown that the bicyclam dose-dependentlyinhibits binding of 125I-labeled SDF-1 to CXCR4 and the signaltransduction (indicated by an increase in intracellular calcium) inresponse to SDF-1. Thus, the bicyclam also functioned as an antagonistto the signal transduction resulting from the binding of stromal derivedfactor or SDF-1α, the natural chemokine to CXCR4. Bicyclams alsoinhibited HIV gp120 (envelope)-induced apoptosis in non-HIV infectedcells (Blanco et al. Antimicrobial Agents and Chemother. 44, 51-56(2000)).

U.S. Pat. Nos. 5,583,131; 5,698,546; 5,817,807; 5,021,409; and 6,001,826which are incorporated herein in their entirety by reference, disclosecyclic compounds that are active against HIV-1 and HIV-2 in in vitrotests. It was subsequently discovered and further disclosed in PCT WO02/34745 that these compounds exhibit anti-HIV activity by binding tothe chemokine receptor CXCR4 expressed on the surface of certain cellsof the immune system. This competitive binding thereby protects thesetarget cells from infection by HIV which utilize the CXCR4 receptor forentry. In addition, these compounds antagonize the binding, signalingand chemotactic effects of the natural ligand for CXCR4, the chemokinestromal cell-derived factor 1α (SDF-1). We further disclosed that thesenovel compounds demonstrate protective effects against HIV infection oftarget cells by binding in vitro to the CCR5 receptor.

Additionally we have disclosed in U.S. Pat. No. 6,365,583 that thesecyclic polyamine antiviral agents described in the above-mentionedpatents/patent applications have the effect of enhancing production ofwhite blood cells as well as exhibiting antiviral properties. Thus,these agents are useful for controlling the side-effects ofchemotherapy, enhancing the success of bone marrow transplantation,enhancing wound healing and burn treatment, as well as combatingbacterial infections in leukemia.

More recently, we disclosed in PCT WO 00/56729, PCT WO 02/22600, PCT WO02/22599, and PCT WO 02/34745 a series of heterocyclic compounds thatexhibit anti-HIV activity by binding to the chemokine receptors CXCR4and CCR5 expressed on the surface of certain cells of the immune system.This competitive binding thereby protects these target cells frominfection by HIV which utilize the CXCR4 or CCR5 receptors for entry. Inaddition, these compounds antagonize the binding, signaling andchemotactic effects of the natural ligand for CXCR4, the chemokinestromal cell-derived factor 1α (SDF-1) and/or the natural ligand forCCR5, the chemokine RANTES.

The chemokine receptor, CXCR-4 has been found to be essential for thevascularization of the gastrointestinal tract (Tachibana, et al., Nature(1998) 393:591-594) as well as haematopoiesis and cerebellar development(Zou, et al., Nature (1998) 393:591-594). Interference with any of theseimportant functions served by the binding of pre-B-cellgrowth-stimulating factor/stromal derived factor (PBSF/SDF-1) to theCXCR-4 chemokine receptor results in lethal deficiencies in vasculardevelopment, haematopoiesis and cardiogenesis. Similarly, fetalcerebellar development appears to rely upon the effective functioning ofCXCR-4 in neuronal cell migration and patterning in the central nervoussystem. This G-protein-coupled chemokine receptor appears to play acritical role in ensuring the necessary patterns of migration of granulecells in the cerebellar anlage.

Herein, we disclose compounds that have unique chemical attributes andthat exhibit protective effects against HIV infection of target cells bybinding to chemokine receptor CXCR4 or CCR5 in a similar manner to thepreviously disclosed macrocyclic compounds. In addition, these compoundsantagonize the binding, signaling and chemotactic effects of the naturalligand for CXCR4, the chemokine stromal cell-derived factor 1α (SDF-1)and/or the natural ligand for CCR5 (the chemokine RANTES).

Citation of the above documents is not intended as an admission that anyof the foregoing is pertinent prior art. All statements as to the dateor representation as to the contents of these documents is based on theinformation available to the applicants and does not constitute anyadmission as to the correctness of the dates or contents of thesedocuments. Further, all documents referred to throughout thisapplication are hereby incorporated in their entirety by referenceherein.

DISCLOSURE OF THE INVENTION

The present invention provides novel compounds that bind chemokinereceptors and interfere with the binding of the natural ligand thereto.The compounds of the present invention are useful as agentsdemonstrating protective effects on target cells from HIV infection, andwhich are useful to treat rheumatoid arthritis. Embodiments of thepresent invention are compounds that act as antagonists or agonists ofchemokine receptors, which are useful as agents capable ofreconstituting the immune system by increasing the level of CD4⁺ cells;as antagonist agents of apoptosis in immune cells, such as CD8⁺ cells,and neuronal cells; as antagonist agents of migration of human bonemarrow B lineage cells to stromal-derived factor 1, as well as otherbiological activities related to the ability of these compounds toinhibit the binding of chemokines to their receptors.

More particularly, the present invention relates to macrocycliccompounds that can be described generally as consisting of a “core”nitrogen atom surrounded by three pendant groups, wherein two of thethree pendant groups are preferably benzimidazolyl methyl andtetrahydroquinolinyl, and the third is a pendant group which contains anadditional nitrogen.

In one aspect, the invention is directed to a compound of the formula

X and Y are independently N or CR¹;

Z is S, O, NR¹ or CR¹ ₂;

each R¹—R⁶ is independently H or a noninterfering substituent;

n1is 0-4;

n2 is 0-1, wherein the * signifies C≡C may be substituted for CR⁵═CR⁵;

n3 is 0-4;

wherein n1+n2+n3 is greater than or equal to 2;

bis0-2;

wherein the following combinations of R groups may be coupled togenerate a ring, which ring may be saturated or unsaturated:

R²+R²

one R²+R³

R³+ one R⁴,

R⁴+R⁴,

one R⁵+ another R⁵,

one R⁵+ one R⁶, and

R⁶+R⁶;

wherein the ring may not be aromatic when the participants in ringformation are two R⁵; and

wherein when n2 is 1, neither n1 nor n3 can be 0.

It should be noted that two R⁵ on the same atom (and two R² or R⁶ on thesame atom) may form a bridge.

Six-membered rings are preferred for ring B, with the preferredcombination of rings A and B being tetrahydroquinolinyl.

Suitable noninterfering substituents include alkyl (C₁₋₁₀), alkenyl(C₂₋₁₀), alkynyl (C₂₋₁₀), aryl (“C”₅₋₁₂), arylalkyl, arylalkenyl, orarylalkynyl, each of which may optionally contain one or moreheteroatoms selected from O, S, and N and each of which may further besubstituted; or optionally substituted forms of acyl, arylacyl, alkyl-alkenyl-, alkynyl- or arylsulfonyl and forms thereof which containheteroatoms in the alkyl, alkenyl, alkynyl or aryl moieties. Othernoninterfering substituents include OR, SR, NR₂, COOR, CONR₂, where R isH or alkyl, alkenyl, alkynyl or aryl as defined above. Where thesubstituted atom is C, the substituents may include, in addition to thesubstituents listed above, halo, OOCR, NROCR, where an R is H or asubstituent set forth above, or may be ═O.

In general, a “noninterfering substituent” is a substituent whosepresence does not destroy the ability of the compound of formula I tobehave as a chemokine. Specifically, the presence of the substituentdoes not destroy the effectiveness of the compound. Because thecompounds of the present invention have been shown to inhibit HIVreplication, and specifically to interact with the CXCR4 receptor, thecompounds of the invention are shown to be effective in treatingconditions which require modulation of CXCR4 and CCR5 mediated activity.

In other aspects, the invention is directed to pharmaceuticalcompositions containing at least one compound of Formula I, and tomethods of ameliorating conditions that are modulated by the CXCR4receptor or the CCR5 receptor. Such conditions include, HIV infection,diseases associated with inflammation, diseases that are associated withimmunosuppression and certain tumors.

MODES OF CARRYING OUT THE INVENTION

The invention provides compounds described above of Formula I which arechemokines and thus modulators of chemokine receptors.

In more detail, the compounds bind chemokine receptors and interferewith the binding of the natural ligand thereto, and demonstrateprotective effects on target cells from HIV infection. The compounds arealso useful as antagonists or agonists of chemokine receptors, and arethus capable of reconstituting the immune system by increasing the levelof CD4⁺ cells; as antagonist agents of apoptosis in immune cells, suchas CD8⁺ cells, and neuronal cells; as antagonist agents of migration ofhuman bone marrow B lineage cells to stromal-derived factor 1, as wellas other biological activities related to the ability of these compoundsto inhibit the binding of chemokines to their receptors.

Chemokine antagonists that interfere in the binding of a chemokine toits receptor are useful to reconstitute the immune system by increasingthe level of CD4⁺ cells (Biard-Piechaczyk, et al., Immunol. Lett., 70:1-3 1999); as antagonist agents of apoptosis in immune cells, such asCD8⁺ cells (Herbin, et al., Nature 395: 189-193, 1998), and asantagonist agents of apoptosis in neuronal cells (Ohagen et al., J. ofVirol., 73: 897-906, 1999; and Hesselgesser, et al., Curr. Biol. 8:595-598, 1998). Chemokine receptor antagonist agents also inhibit themigration of human bone marrow B lineage cells to stromal-derived factor1 (See, for example: E. Fedyk, et al., J of Leukocyte Biol., 66:667-783,1999).

The invention includes pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula I along withat least one excipient, and methods of treating diseases of the humanbody or the bodies of other mammals with such compositions. Theinvention provides a method for blocking or interfering with the bindingby a chemokine receptor with its natural ligand, comprising contactingof said chemokine receptor with an effective amount of the compoundaccording to Formula I. Also included is a method of protecting targetcells possessing chemokine receptors, the binding to which by apathogenic agent results in disease or pathology, comprisingadministering to a mammalian subject a pharmaceutical compositioncomprising a therapeutically effective amount of the compound accordingto Formula I. The invention includes the use of a compound of Formula Iin the manufacture of a medicament for the treatment of a disease inwhich blocking or interfering with binding of a chemokine receptor withits natural ligand is advantageous. The compound is formulated into acomposition in amount corresponding to a therapeutically effectiveamount of a compound of Formula I.

The Invention Compounds

The invention compounds are described generally by Formula I which isreproduced below for purposes of the present discussion.

In one embodiment, the compounds of the present invention are of FormulaII:

or the salts and pro-drug forms thereof, representing a subset of thecompounds of Formula I wherein b is 1, X is CR¹, Y is N, and Z is CR¹ ₂and R¹ to R⁶ and n1-n3 are as defined for Formula I. In this subgenus,the preferred tetrahydroquinolyl and imidazoleibenzimidazolyl methylgroups are attached to the core nitrogen.

In one embodiment, no rings are formed in the portion of the moleculecontaining the non-core nitrogen (that to which two R⁶ are coupled). Inanother embodiment, any two R⁵ (including two R⁵ on the same C), two R⁶or one R⁵ and one R⁶ can be joined together via a 1-6 membered linker toform a ring. Also contemplated are rings formed by two R², by one R² andR³, and by R³ and one R⁴. Exemplary rings include, inter alia,cycloalkyl, cycloalkenyl, saturated or partially saturated heterocycles(piperidine, piperazine, pyrrolidine, pyrroline, pyrazolidine,imidazoline, morpholine, thiomorpholine, pyrazoline, tetrahydrofliran,dihydrofiran, tetrahydrothiophene, dihydrothiophene, dihydropyran,tetrahydropyran and the like). However, rings formed from two R⁵ fromother than the same C cannot be aromatic.

Thus, alternatively, the present invention provides compounds ofFormulas IIIa-IIIe:

or salts or pro-drug forms thereof wherein:

d=0-3 and n4 is 2-6

especially wherein both R⁶ are H or one R⁶ is H and the other includesan aryl moiety, or wherein two R⁶ form a ring.

The compounds may be supplied as “pro-drugs”, that is, protected forms,which release the compound after administration to a subject. Forexample, the compound may carry a protective group which is split off byhydrolysis in body fluids, e.g., in the bloodstream, thus releasingactive compound or is oxidized or reduced in body fluids to release thecompound. A discussion of pro-drugs may be found in “Smith and Williams'Introduction to the Principles of Drug Design,” H. J. Smith, Wright,Second Edition, London 1988.

The compounds may also be supplied as salts with organic or inorganicacids or bases that are nontoxic. Non-toxic in the present sense has tobe considered with reference to the prognosis for the infected patientwithout treatment. Examples of inorganic bases with alkali metalhydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), alkalineearth metal hydroxides (e.g., of calcium, magnesium, etc.), andhydroxides of aluminum, ammonium, etc. Examples of organic bases includetrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, etc. Examples of inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, etc. Examples of organic acids include formic acid,oxalic acid, acetic acid, tartaric acid, methanesulfonic acid,benzenesulfonic acid, malic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, etc. Also included are salts with basicamino acids such as arginine, lysine, ornithine, etc., and salts withacidic amino acids such as aspartic acid, glutamic acid, etc.

All of the compounds of the invention contain at least one chiralcenter. The invention includes mixtures of stereoisomers, individualstereoisomers, and enantiomeric mixtures, and mixtures of multiplestereoisomers. In short, the compound may be supplied in any desireddegree of chiral purity.

As set forth above, the basic structure of the compounds of theinvention is defined by Formula I, and particular illustrativeembodiments are found in Formulas I-III. The further definition of thecompounds of the invention rest on the identification of thenoninterfering substituents.

Preferred embodiments of R¹ include H, halo, alkyl, alkoxy, CF₃, and thelike. Preferably, all R¹ are H or one R¹ is other than H and theremaining two R¹ are H.

Preferred embodiments of R² include H alkyl, and alkenyl especially Hand methyl.

Preferred embodiments of R³ include H, alkyl, alkenyl, arylalkyl, andaryl.

Preferred embodiments of R⁴ include H, alkyl, alkenyl and especiallythose wherein the two R⁴ are bridged to form an aromatic ring so thatthe substituent on the core nitrogen is benzimidazolylmethyl, includinga further heteroatom-containing form thereof.

Preferred embodiments of R⁵ include H, alkyl and alkenyl, eachoptionally substituted, including those wherein alkyl or alkenylsubstituents on a single carbon or on adjacent or nonadjacent carbonsform a saturated or unsaturated ring. This ring cannot be aromatic.Alternative embodiments for R⁵, oximes, alkylated oximes hydroxylamine,including alkylated hydroxylamine, halo and the like.

Preferred embodiments of R⁶ include H, arylalkyl, arylsulfonyl,including those wherein one or more nitrogen atoms is present in thering, and including fused ring aryl groups such as indolyl. Alsopreferred for R⁶ are heteroatom containing groups such as guanidylgroups carboxyl and carbamino groups, amides, arylsulfonic acids andaryl acyl substituents, again including aryl groups which comprise oneor more nitrogens, alkenyl, cycloalkyl, carboxyl, and optionallysubstitutes, alkyl and alkenyl moieties, including those that aresubstituted by alcohols or amines are also preferred. Two R⁶ may form asaturated, unsaturated or aromatic ring, optionally including one ormore N, O and/or S. An R⁵ and an R⁶ or two R⁶ may also constitute ashared alkylene or alkenylene bridge to obtain the saturated orunsaturated ring, which may, be aromatic. In all cases (R⁵+R⁵ or R⁵+R⁶or R⁶+R⁶), the shared alkylene or alkenylene substituent may include oneor more heteroatoms such as N, S or O.

It is preferred, that only 1-3, preferably 1-2 of the R⁵ groups be otherthan hydrogen. In one embodiment, all R⁵ are hydrogen, in anotherembodiment, one pair of R⁵ is a shared alkylene, alkenylene, or suchmoieties which include a heteroatom.

Examples of optionally substituted alkyl groups include methyl, ethyl,propyl, etc. and including cycloalkyls such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc.; examples of optionallysubstituted alkenyl groups include allyl, crotyl, 2-pentenyl, 3-hexenyl,2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,2-cyclohexenylmethyl, etc.; C₁₋₆ alkyl and alkenyl are preferred.

Examples of halogen include fluorine, chlorine, bromine, iodine, etc.,with fluorine and chlorine preferred.

Examples of optionally substituted hydroxyl and thiol groups includeoptionally substituted alkyloxy or alkylthio (e.g., C₁₋₁₀ alkyl) such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc.); an optionally substituted arylalkyloxy orarylalkylthio (e.g., phenyl-C₁₋₄ alkyl, e.g., benzyl, phenethyl, etc.).Where there are two adjacent hydroxyl or thiol substituents, theheteroatoms may be connected via an alkylene group such as O(CH₂)_(n)Oand S(CH₂)_(n)S (where n=1-5). Examples include methylenedioxy,ethylenedioxy, etc. Oxides of thio-ether groups such as sulfoxides andsulfones are also envisioned.

Examples of optionally substituted hydroxyl groups also includeoptionally substituted C₂₋₄alkanoyl (e.g., acetyl, propionyl, butyryl,isobutyryl, etc.), C₁₋₄ alkylsufonyl (e.g., methanesulfonyl,ethanesulfonyl, etc.) and an optionally substituted aromatic andheterocyclic carbonyl group including benzoyl, pyridinecarbonyl etc.

Substituents on optionally substituted amino groups may bind to eachother to form a cyclic amino group (e.g., 5- to 6-membered cyclic amino,etc. such as tetrahydropyrrole, piperazine, piperidine, pyrrolidine,morpholine, thiomorpholine, pyrrole, imidazole, etc.). Said cyclic aminogroup may have a substituent, and examples of the substituents includehalogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, thiol group, amino group, carboxyl group, an optionallyhalogenated C₁₋₄ alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), anoptionally halogenated C₁₋₄ alkoxy (e.g., methoxy, ethoxy,trifluoromethoxy, trifluoroethoxy, etc.), C₂₋₄ alkanoyl (e.g., acetyl,propionyl, etc.), C₁₋₄ alkylsulfonyl (e.g., methanesulfonyl,ethanesulfonyl, etc.) the number of preferred substituents are 1 to 3.

An amino group may also be substituted once or twice (to form asecondary or tertiary amine) with a group such as an optionallysubstituted alkyl group including C₁₋₁₀alkyl (e.g., methyl, ethyl propyletc.); an optionally substituted alkenyl group such as allyl, crotyl,2-pentenyl, 3-hexenyl, etc., or an optionally substituted cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc. In these cases, C1-6 alkyl, alkenyl and cycloalkyl arepreferred. The amine group may also be optionally substituted with anaromatic or heterocyclic group, aralkyl (e.g., phenyl C₁₋₄alkyl) orheteroalkyl for example, phenyl, pyridine, phenylmethyl (benzyl),phenethyl, pyridinylmethyl, pyridinylethyl, etc. The heterocyclic groupmay be a 5 or 6 membered ring containing 1-4 heteroatoms.

An amino group may be substituted with an optionally substituted C2-4alkanoyl, e.g., acetyl, propionyl, butyryl, isobutyryl etc., or aC₁₋₄alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) or acarbonyl or sulfonyl substituted aromatic or heterocyclic ring, e.g.,benzenesulfonyl, benzoyl, pyridinesulfonyl, pyridinecarbonyl etc. Theheterocycles are as defined above.

Examples of optionally substituted carbonyl groups, or sulfonyl groupsinclude optionally substituted forms of such groups formed from varioushydrocarbyls such as alkyl, alkenyl and 5- to 6-membered monocyclicaromatic group (e.g., phenyl, pyridyl, etc.), as defined above.

Utility and Administration

The invention is directed to compounds of Formula I that modulatechemokine receptor activity. Chemokine receptors include but are notlimited to CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4.

In one embodiment, the invention provides compounds of Formula I thatdemonstrate protective effects on target cells from HIV infection bybinding specifically to the chemokine receptor thus affecting thebinding of a natural ligand to the CCR-5 and/or CXCR-4 of a target cell.

In another embodiment, the compounds of the present invention are usefulas agents which affect chemokine receptors, such as CCR-1, CCR-2, CCR-3,CCR-4, CCR-5, CXCR-3, CXCR-4 where such chemokine receptors have beencorrelated as being important mediators of many inflammatory as well asimmunoregulatory diseases.

Other diseases that are also implicated with chemokines as mediatorsinclude angiogenesis, and tumorigenesis such as brain, and breasttumors. Thus, a compound that modulates the activity of such chemokinereceptors is useful for the treatment or prevention of such diseases.

The term “modulators” as used herein is intended to encompassantagonist, agonist, partial antagonist, and or partial agonist, i.e.,inhibitors, and activators. In one embodiment of the present invention,compounds of Formula I demonstrate a protective effect against HIVinfection by inhibiting the binding of HIV to a chemokine receptor suchas CCR-5 and/or CXCR-4, of a target cell. Such modulation is obtained bya method which comprises contacting a target cell with an amount of thecompound which is effective to inhibit the binding of the virus to thechemokine receptor.

Compounds that inhibit chemokine receptor activity and function may beused for the treatment of diseases that are associated withinflammation, including but are not limited to, inflammatory or allergicdiseases such as asthma, allergic rhinitis, hypersensitivity lungdiseases, hypersensitivity pneumonitis, eosinophilic pneumonias,delayed-type hypersensitivity, interstitial lung disease (ILD) (e.g.,idiopathic pulmonary fibrosis, or ILD associated with rheumatoidarthritis, systemic lupus erythematosus, ankylosing spondylitis,systemic sclerosis, Sjogren's syndrome, polymyositis ordermatomyositis); systemic anaphylaxis or hypersensitivity responses,drug allergies, insect sting allergies; autoimmune diseases, such asrheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus,myastenia gravis, juvenile onset diabetes; glomerulonephritis,autoimmune throiditis, graft rejection, including allograft rejection orgraft-versus-host disease; inflammatory bowel diseases, such as Crohn'sdisease and ulcerative colitis; spondyloarthropathies; scleroderma;psoriasis (including T-cell mediated psoriasis) and inflammatorydermatoses such as dermatitis, eczema, atopic dermatitis, allergiccontact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous,and hypersensitivity vasculitis); eosinphilic myotis, eosiniphilicfasciitis; and cancers.

In addition compounds that activate or promote chemokine receptorfunction are used for the treatment of diseases that are associated withimmunosuppression such as individuals undergoing chemotherapy, radiationtherapy, enhanced wound healing and burn treatment, therapy forautoimmune disease or other drug therapy (e.g., corticosteroid therapy)or combination of conventional drugs used in the treatment of autoimmunediseases and graft/transplantation rejection, which causesimmunosuppression; immunosuppression due to congenital deficiency inreceptor function or other causes; and infectious diseases, such asparasitic diseases, including but not limited to helminth infections,such as nematodes (round worms); Trichuriasis, Enterobiasis, Ascariasis,Hookworm, Strongyloidiasis, Trichinosis, filariasis; trematodes;visceral worms, visceral larva migtrans (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larvamigrans (Ancylostona braziliense, Ancylostoma caninum); themalaria-causing protozoan Plasmodium vivax, Human cytomegalovirus,Herpesvirus saimiri, and Kaposi's sarcoma herpesvirus, also known ashuman herpesvirus 8, and poxvirus Moluscum contagiosum.

Compounds of the present invention may be used in combination with anyother active agents or pharmaceutical compositions where such combinedtherapy is useful to modulate chemokine receptor activity and therebyprevent and treat inflammatory and immunoregulatory diseases.

The compounds may further be used in combination with one or more agentsuseful in the prevention or treatment of HIV. Examples of such agentsinclude:

(1) nucleotide reverse transcriptase inhibitor such as tenofovirdisoproxil fumarate; lamivudine/zidovudine;abacavir/lamivudine/zidovudine; emtricitabine; amdoxovir; alovudine;DPC-817; SPD-756; SPD-754; GS7340; ACH-126,443 (beta)-L-F d4C;didanosine, zalcitabine, stavudine, adefovir, adefovir dipivoxil,fozivudine todoxil, etc.;

(2) non-nucleotide reverse transcriptase inhibitor (including an agenthaving anti-oxidation activity such as immunocal, oltipraz, etc.) suchas nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz,TMC-125; DPC-083; capravarine; calanolide A; SJ-3366 series, etc.;

(3) protease inhibitors such as saquinavir, lopinavir/ritonavir,atazanavir, fosamprenavir, tipranavir, TMC-114, DPC-684, indinavir,nelfmavir, amprenavir, palinavir, lasinavir, etc.;

(4) entry inhibitors such as T-20; T-1249; PRO-542; PRO-140; TNX-355;BMS-806 series; and 5-Helix;

(5) CCR5-receptor inhibitors such as Sch-C (or SCH351125); Sch-D, andSCH350634; TAK779; UK 427,857 and TAK 449;

(6) Integrase inhibitors such as L-870,810; GW-810781 (S-1360); and

(7) Budding inhibitors such as PA-344; and PA-457.

Combinations of compounds of the present invention with HIV agents isnot limited to (1), (2), and or (3), but includes combination with anyagent useful for the treatment of HIV. Combinations the compounds of theinvention and other HIV agents may be administered separately or inconjunction. The administration of one agent may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Like the compounds of the present invention, AMD3100 is an antagonistwith the CXCR4 chemokine receptor (Gerlach, et al., J. Biol. Chem.(2001) 276:14153-14160). These compounds interfere with the binding ofbone marrow stromal cell derived SDF-1 with CXCR4 on stem cells whichleads to the release of hematopoietic stem cells from bone marrow intothe circulation (Broxmeyer, et al., Blood (2001) 98:811a (Abstract)). Ina Phase 1 study at the University of Washington, Seattle, a single doseof 80 μg/kg of AMD-3100 resulted in a WBC count of 17,000/μl and a peak6-fold increase in circulating CD34+ progenitor/stem cells at the 6 hourtime point (Liles, et al., Blood (2001) 98:737a (Abstract)). In anotherrecent study mice were injected with rhG-CSF and recombinant rat StemCell Factor (rrSCF) in order to mobilize large numbers of bone marrowstem cells into the circulation and then we induced a heart attack. Thecombination of rrSCF and rhG-CSF provides a peak number of circulatingstem cells after 5 daily injections. At 27 days post surgery there was a68% improvement in survival in the treated group versus the controls. Atthis time the dead tissue was replaced with regenerating myocardium andall functional parameters tested were improved compared with controls(Orlic, et al., PNAS (2001) 98:10344-10349).

Thus, the compounds of the invention are useful to stimulate theproduction and proliferation of stem cells and progenitor cells.

The compounds of the invention may be prepared in the form of prodrugs,i.e., protected forms which release the compounds of the invention afteradministration to the subject. Typically, the protecting groups arehydrolyzed in body fluids such as in the bloodstream thus releasing theactive compound or are oxidized or reduced in vivo to release the activecompound. A discussion of prodrugs is found in Smith and WilliamsIntroduction to the Principles of Drug Design, Smith, H. J.; Wright,2^(nd) ed., London (1988).

The compounds of the invention, as they are polyamines, may beadministered prepared in the forms of their acid addition salts or metalcomplexes thereof. Suitable acid addition salts include salts ofinorganic acids that are biocompatible, including HCl, HBr, sulfuric,phosphoric and the like, as well as organic acids such as acetic,propionic, butyric and the like, as well as acids containing more thanone carboxyl group, such as oxalic, glutaric, adipic and the like.Typically, at physiological pH, the compounds of the invention will bein the forms of the acid addition salts. Particularly preferred are thehydrochlorides. In addition, when prepared as purified forms, thecompounds may also be crystallized as the hydrates.

The compounds of the invention may be administered as sole activeingredients, as mixtures of various compounds of formula (1), and/or inadmixture with additional active ingredients that are therapeutically ornutritionally useful, such as antibiotics, vitamins, herbal extracts,anti-inflammatories, glucose, antipyretics, analgesics,granulocyte-macrophage colony stimulating factor (GM-CSF), Interleukin-1(IL-1), Interleukin-3 (IL-3), Interleukin-8 (IL-8), PIXY-321(GM-CSF/IL-3 fusion protein), macrophage inflammatory protein, stem cellfactor, thrombopoietin, growth related oncogene or chemotherapy and thelike.

The compounds of the invention may be formulated for administration toanimal subject using commonly understood formulation techniques wellknown in the art. Formulations which are suitable for particular modesof administration and for compounds of the type represented by those offormula (1) may be found in Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Company, Easton, Pa.

Preferably, the compounds are administered by injection, most preferablyby intravenous injection, but also by subcutaneous or intraperitonealinjection, and the like. Additional parenteral routes of administrationinclude intramuscular and intraarticular injection. For intravenous orparenteral administration, the compounds are formulated in suitableliquid form with excipients as required. The compositions may containliposomes or other suitable carriers. For injection intravenously, thesolution is made isotonic using standard preparations such as Hank'ssolution.

Besides injection, other routes of administration may also be used. Thecompounds may be formulated into tablets, capsules, syrups, powders, orother suitable forms for administration orally. By using suitableexcipients, these compounds may also be administered through the mucosausing suppositories or intranasal sprays. Transdermal administration canalso be effected by using suitable penetrants and controlling the rateof release.

The formulation and route of administration chosen will be tailored tothe individual subject, the nature of the condition to be treated in thesubject, and generally, the judgment of the attending practitioner.

Suitable dosage ranges for the compounds of formula (1) vary accordingto these considerations, but in general, the compounds are administeredin the range of about 0.1 μg/kg-5 mg/kg of body weight; preferably therange is about 1 μg/kg-300 μg/kg of body weight; more preferably about10 μg/kg-100 μg/kg of body weight. For a typical 70-kg human subject,thus, the dosage range is from about 0.7 μg-350 mg; preferably about 700μg-21 mg; most preferably about 700 μg-7 mg. Dosages may be higher whenthe compounds are administered orally or transdermally as compared to,for example, i.v. administration.

The compounds may be administered as a single bolus dose, a dose overtime, as in i.v. or transdermal administration, or in multiple dosages.

In addition to direct administration to the subject, the compounds offormula (1) can be used in ex vivo treatment protocols to prepare cellcultures which are then used to replenish the blood cells of thesubject. Ex vivo treatment can be conducted on autologous cellsharvested from the peripheral blood or bone marrow or from allograftsfrom matched donors. The concentration of the compound or compounds offormula (1) alone or in combination with other agents, such asmacrophage inflammatory protein is a matter of routine optimization.

Subjects that will respond favorably to the method of the inventioninclude medical and veterinary subjects generally, including humanpatients. Among other subjects for whom the methods of the invention isuseful are cats, dogs, large animals, avians such as chickens, and thelike. In general, any subject who would benefit from an elevation ofprogenitor cells and/or stem cells, or whose progenitor cells and/orstem cells are desirable for stem cell transplantation are appropriatefor administration of the invention method.

Typical conditions which may be ameliorated or otherwise benefited bystimulation of hematopoiesis, include hematopoietic disorders, such asaplastic anemia, leukemias, drug-induced anemias, and hematopoieticdeficits from chemotherapy or radiation therapy. The compounds of theinvention are also useful in enhancing the success of transplantationduring and following immunosuppressive treatments as well as ineffecting more efficient wound healing and treatment of bacterialinflammation, and for treating subjects who are immuno-compromised orwhose immune system is otherwise impaired. Typical conditions which areameliorated or otherwise benefited by hematopoiesis stimulation includethose subjects who are infected with a retrovirus and more specificallywho are infected with human immunodeficiency virus (HIV). The compoundsof the invention thus target a broad spectrum of conditions for whichelevation of progenitor cells and/or stem cells in a subject would bebeneficial or, where harvesting of progenitor cells and/or stem cell forsubsequent stem cell transplantation or transfusion would be beneficial.

The invention compounds are also administered to regenerate myocardiumby mobilizing bone marrow stem cells.

The compounds according to the present invention may be administered byoral, intramuscular, intraperitoneal, intravenous, intracistemalinjection or infusion, subcutaneous injection, transdermal ortransmucosal administration or by implant. They may also be administeredby inhalation spray, nasal, vaginal, rectal, sublingual, or topicalroutes and may be formulated, alone or together, in suitable dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles appropriate for each routeof administration.

The compounds of the invention are used to treat animals, includingmice, rats, horses, cattle, sheep, dogs, cats, and monkeys. Thecompounds of the invention are also effective for use in humans.

EXAMPLES

The intermediates 8-hydroxy-5,6,7,8-tetrahydroquinoline and8-amino-5,6,7,8-tetrahydroquinoline were prepared according to theprocedures described in Bridger et al. PCT Patent Application WO00/56729. The intermediateN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanaminewas prepared as described by Bridger et al, U.S. Patent ApplicationsSer. No. 60/232,891, U.S. Ser. No. 60/234,510. The intermediate1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole was prepared asdescribed by An, H.; Wang, T.; Mohan, V.; Griffey, R. H.; Cook, P. D.Tetrahedron 1998, 54, 3999-4012.

General Synthesis Procedures:

General Procedure for N-Alkylation of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-aminewith Mesylates or Alkyl Chlorides

To a solution of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(or amine) (1-1.4 equivalents), N,N,-diisopropylethylamine (or K₂CO₃)(1.5-2 equivalents) and KI (0.05-0.16 equivalent) in CH₃CN(concentration ˜0.1-0.2 M) was added the mesylate or alkyl chloride(such as 1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole) (1-1.4equivalents) and the mixture stirred at 50-70° C. for 3-25 hours, asmonitored by analytical thin layer chromatography. The reaction mixturewas cooled, diluted with CH₂Cl₂ (10 mL/mmol amine) and poured intoeither saturated aqueous NaHCO₃ or brine (10 mL/mmol alcohol). Thephases were separated and the aqueous phase extracted with CH₂Cl₂ (3×10mL/mmol amine). The combined organic phases were dried (Na₂SO₄ or MgSO₄)and concentrated under reduced pressure. The crude material was purifiedby chromatography to afford the desired N-alkylated product.

General Procedure A: Direct Reductive Amination with NaBH₃CN

To a stirred solution of the amine (1 equivalent) in anhydrous methanol(concentration ˜0.1 M), at room temperature, was added the carbonylcompound (˜1-2 equivalents) in one portion. Once the carbonyl haddissolved (˜5 minutes), NaBH₃CN (˜2-4 equiv.) was added in one portionand the resultant solution was stirred at room temperature. The solventwas removed under reduced pressure and CH₂Cl₂ (20 mL/mmol of amine) andbrine or 1.0 M aqueous NaOH (10 mL/mmol amine) were added to theresidue. The phases were separated and the aqueous phase was extractedwith CH₂Cl₂ (3×10 mL/mmol amine). The combined organic phases were dried(Na₂SO₄) and concentrated under reduced pressure. The crude material waspurified by chromatography.

General Procedure B: Direct Reductive Amination with NaBH(OAc)₃ or NaBH₄

To a stirred solution of the amine (1 equivalent) in CH₂Cl₂(concentration ˜0.2 M), at room temperature, was added the carbonylcompound (˜1-2 equivalents), glacial acetic acid (0-2 equivalents) andNaBH(OAc)₃ (˜1.5-3 equivalents) and the resultant solution stirred atroom temperature. The reaction mixture was poured into either saturatedaqueous NaHCO₃ or 1.0 M aqueous NaOH (10 mL/mmol amine). The phasesseparated and the aqueous phase extracted with CH₂Cl₂ (3×10 mL/mmolamine). The combined organic phases were dried (Na₂SO₄) and concentratedunder reduced pressure. The crude material was purified bychromatography.

Similarly, to a stirred solution of the amine (1 equivalent) inanhydrous MeOH (concentration ˜0.1 M), at room temperature, was addedthe carbonyl compound (1 equivalent). The resultant solution was stirredat room temperature or heated to reflux for 4-24 hours. NaBH₄ (1-2equivalents) was added and the resultant mixture stirred at roomtemperature for ˜20 minutes. The reaction mixture was concentrated,dissolved in CH₂Cl₂, washed consecutively with saturated aqueous NaHCO₃and saturated aqueous NaCl. The aqueous layers were extracted withCH₂Cl₂ (2×) and the combined organic extracts were dried (MgSO₄) andconcentrated.

General Procedure C: Reaction of Alcohols with Methanesulfonyl Chloride

To a stirred solution of the alcohol (1 equivalent) and Et₃N (1.5-2equivalents) in CH₂Cl₂ (or THF) (concentration ˜0.1 M) at roomtemperature (or 0° C.) was added methanesulfonyl chloride (˜1.5equivalents) and the reaction stirred at room temperature for 0.5-1 h.The reaction mixture was poured into either saturated aqueous NaHCO₃ orsaturated NH₄Cl (10 mL/mmol alcohol). The phases were separated and theaqueous phase extracted with CH₂Cl₂ (3×10 mL/mmol amine). The combinedorganic phases were dried (Na₂SO₄) and concentrated under reducedpressure. The crude material was either purified by chromatography orused without further purification in the N-alkylation step.

General Procedure D: Salt Formation Using Saturated HBr(g) in AceticAcid:

To a solution of the free base in glacial acetic acid (2 mL) was added,a saturated solution of HBr(g) in acetic acid (2 mL). A large volume ofether (25 mL) was then added to precipitate a solid, which was allowedto settle to the bottom of the flask and the supernatant solution wasdecanted. The solid was washed by decantation with ether (3×25 mL) andthe remaining traces of solvent were removed under vacuum. Foradditional purification, the solid was dissolved in methanol andre-precipitated with a large volume of ether. Washing the solid withether by decantation, followed by drying of the solid in vacuo (0.1Torr) gave the desired compound.

Intermediates:

Preparation of 4-hydroxymethylbenzaldehyde

Terephthaldicarboxaldehyde (30.02 g, 224 mmol), methanol (200 mL),palladium on activated carbon, (10%, 3.02 g) and 2-(aminomethyl)pyridine(2.3 mL, 22 mol, 0.01 mol equiv) were combined in a hydrogenation vesseland the reaction mixture was shaken on a Parr hydrogenator for 2.5 hoursat 40 psi of hydrogen. The mixture was filtered through celite, the cakewashed with methanol and the solvent from the eluent removed in vacuo.Purification of the crude product by column chromatography on silica gel(EtOAc/Hexanes, 1:1) afforded the title compound (23.8 g, 78%) as awhite solid. ¹H NMR (CDCl₃) δ 4.80 (s, 2H), 7.53 (d, 2H, J=9 Hz), 7.87(d, 2H, J=9 Hz), 10.00 (s, 1H).

Preparation of 6,7-Dihydro-5H-quinolin-8-one

To a stirred solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline (13.96 g,93.6 mmol) in dry CH₂Cl₂ (400 mL) was added activated manganese dioxide(85% purity, 82.22 g, 804 mmol). The resulting heterogeneous mixture wasstirred 18 h, at which point the black slurry was filtered through acake of celite and washed with CH₂Cl₂ (3×50 mL). The combined washingswere concentrated to afford 11.27 g (82%) of the title compound as apale yellow solid, which was used in subsequent reactions withoutfurther purification. ¹H NMR (CDCl₃) δ 2.17-2.25 (m, 2H), 2.82 (t, 2H,J=7 Hz), 3.04 (t, 2H, J=6 Hz), 7.37 (dd, 1H, J=9, 6 Hz), 7.66 (dd, 1H,J=9, 1 Hz), 8.71 (dd, 1H, J=6, 1 Hz); ¹³C NMR (CDCl₃) δ 22.2, 28.6,39.2, 126.6 137.3, 140.5, 147.6, 148.6, 196.5. ES-MS m/z 148 (M+H).

Preparation of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

Using General Procedure for N-Alkylation: To a stirred solution of8-amino-5,6,7,8-tetrahydroquinoline (7.34 g, 49.6 mmol) in dry CH₃CN(250 mL) was added 1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole(13.22 g, 49.6 mmol), N,N-diisopropylethylamine (15.5 mL, 89.2 mmol) andpotassium iodide (0.41 g, 8.2 mmol) and the mixture was stirred at 60°C. for 3.5 h. Purification by column chromatography on silica gel(CH₂Cl₂/MeOH, 99:1 followed by 97:3 and 96:4) gave the intermediateamine (6.38 g, 34%) as an orange, sticky oil. ¹H NMR (CDCl₃) δ 1.76 (s,9H), 1.81-2.10 (m, 2H), 2.25-2.37 (m, 1H), 2.72-2.89 (m, 2H), 3.77-3.84(m, 1H), 4.39 (d, 1H, J=15.0 Hz), 4.56 (d, 1H, J=15.0 Hz), 7.00-7.06 (m,1H), 7.27-7.37 (m, 1H), 7.64-7.74 (m, 1H), 7.90-7.96 (d, 2H, J=8.1 Hz),8.34 (d, 1H, J=3.0 Hz); ¹³C NMR (CDCl₃) δ 20.13, 28.48, 29.00, 29.20,47.15, 56.89, 86.20, 115.32, 120.28, 122.06, 124.43, 124.85, 132.77,133.74, 137.01, 142.44, 147.10, 149.22, 154.90, 157.72; ES-MS m/z 279(M+H-boc).

Preparation of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

To a stirred solution of (2-aminomethyl)benzimidazole dihydrochloridehydrate (5.96 g, 27.1 mmol) in dry MeOH (225 mL) was added6,7-dihydro-5H-quinolin-8-one (3.99 g, 27.1 mmol) and the mixturestirred at room temperature for 69 h. To the resultant solution wasadded sodium borohydride (2.06 g, 54.2 mmol) in two portions and themixture stirred for 1.5 h. The reaction mixture was concentrated invacuo and diluted with CH₂Cl₂ (150 mL). The organic layer was washedwith saturated aqueous sodium bicarbonate (200 mL), the aqueous layerextracted with CH₂Cl₂ (2×50 mL) and the combined organic layers dried(Na₂SO₄), filtered, and concentrated in vacuo. Purification by columnchromatography on silica gel (CH₂Cl₂/MeOH, 99:1 followed by 98:2 and96:4) gave the intermediate amine (3.59 g, 50%) as a yellow foam. ¹H NMR(CDCl₃) δ 1.66-1.90 (m, 3H), 1.91-2.00 (m, 1H), 2.00-2.17 (m, 1H),2.33-2.69 (br m, 1H), 3.88-3.96 (m, 1H), 4.37 (d, 1H, J=3.0 Hz),7.18-7.26 (m, 4H), 7.48 (d, 1H, J=6.0 Hz), 7.58-7.78 (br m, 1H),8.55-8.58 (m, 1H); ¹³C NMR (CDCl₃) δ 19.66, 29.12, 30.24, 46.62, 57.28,122.21, 122.83, 133.55, 138.07, 146.98, 156.17, 157.73.

Preparation of 1-(2-trimethylsilylethoxymethyl)-2-formyl-benzimidazole

To a stirred solution of 2-hydroxymethylbenzimidazole (31.94, 0.216 mol)in dry DMF (450 mL) was added N,N-diisopropylethylamine (90 mL, 0.52mol) followed by 2-(trimethylsily)ethoxymethyl chloride (75% in pentane,55 g, 0.25 mol) and the mixture heated to 60° C. for 2 h. The mixturewas cooled to room temperature, concentrated under reduced pressure andpartitioned between EtOAc (400 mL) and distilled water (700 mL). Thephases were separated and the aqueous layer extracted with EtOAc (2×200mL). The combined organic extracts were washed with brine (1×400 mL),dried (Na₂SO₄), filtered and concentrated under reduced pressure.Purification of the crude oil by column chromatography on silica gel (4%MeOH/CH₂Cl₂) afforded the desired1-(2-trimethylsilylethoxymethyl)-2-hydroxymethylbenzimidazole (26.28 g,44%) as a yellow oil. ¹H NMR (CDCl₃) δ −0.04 (s, 9H), 0.89 (t, 2H, J=9Hz), 1.75 (br s, 1H), 3.55 (t, 2H, J=9 Hz), 4.94 (s, 2H), 7.26-7.30 (m,2H), 7.43-7.45 (m, 1H), 7.70-7.72 (m, 1H).

To a stirred solution of the alcohol from above (26.58 g, 0.096 mol) indry CH₂Cl₂ (450 mL) was added activated MnO₂ (<5 micron, ˜85%, 93 g,0.91 mol) and the suspension stirred at room temperature overnight. Themixture was filtered through celite© (175 g) and the cake was washedwith CH₂Cl₂. The solvent was removed from the eluent under reducedpressure and the resultant residue purified by column chromatography onsilica gel (3% MeOH/CH₂Cl₂) to provide the title aldehyde (14.41 g, 55%)as a pale yellow oil. ¹H NMR (CDCl₃) δ −0.07 (s, 9H), 0.90 (t, 2H, J=9Hz), 3.56 (t, 2H, J=9 Hz), 6.04 (s, 2H), 7.43-7.51 (m, 2H), 7.66 (d, 1H,J=9 Hz), 7.95 (d, 1H, J=9 Hz), 10.13 (s, 1H); ¹³C NMR (CD₃OD) δ −1.19,17.94, 66.62, 73.30, 112.22, 122.51, 124.64, 127.43, 136.62, 143.11,146.39, 185.10; ES-MS m/z (M+H);

Preparation of[1-(2-trimethylsilylethoxymethyl)-1H-Benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

To a stirred solution of1-(2-trimethylsilylethoxymethyl)-2-formyl-benzimidazole (4.26 g, 15.4mmol) in dry MeOH (50 mL) was added a solution of8-amino-5,6,7,8-tetrahydroquinoline (2.20 g, 14.8 mmol) in dry MeOH (20mL) and the mixture stirred for 2 h at room temperature under an argonatmosphere. The reaction mixture was concentrated under reduced pressureand the resultant residue analyzed by ¹H NMR to confirm imine formation.The residue was re-dissolved in dry MeOH (80 mL) and to the resultantsolution was added sodium borohydride (1.17 g, 30.8 mmol). The mixturewas stirred for 5 h, concentrated in vacuo and diluted with CH₂Cl₂ (100mL) and saturated aqueous NaHCO₃ (125 mL). The phases were separated andthe aqueous layer was extracted with CH₂Cl₂ (2×75 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the crude material through a plug of silica gel(CH₂Cl₂/MeOH 96:4) afforded the desired amine (5.91 g, 98%) as an orangeoil. ¹H NMR (CDCl₃) δ −0.07 (s, 9H), 0.90 (t, 2H, J=9 Hz), 1.72-1.83 (m,2H), 1.95-2.01 (m, 1H), 2.76-2.85 (m, 2H), 3.54 (t, 2H, J=9 Hz), 4.33(m, 2H), 5.68 (d, 1H, J=12 Hz), 5.75 (d, 1H, J=12 Hz), 7.05-7.09 (m,1H), 7.25-7.30 (m, 2H), 7.38 (d, 1H, J=9 Hz), 7.44-7.46 (m, 1H),7.71-7.73 (m, 1H), 8.36-8.38 (m, 1H).

Preparation ofN¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-N¹-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-ylmethyl]-butane-1,4-diamine

A solution of(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoirmidazol-2-ylmethyl]-amine(2.86 g, 6.93 mmnol), broimobutyronitrile (1.4 mL, 14.1 mmol) and DIPEA(3.0 mL, 17.2 mmol) in CH₃CN (75 mL) was stirred at 80° C. for 2 days.KI (54 mg, 0.33 mmol) was added and the resultant mixture stirred at 80°C. for 20 hours. The mixture was concentrated under reduced pressure,diluted with CH₂Cl₂ (100 mL) and washed with saturated aqueous NaCl. Theaqueous layer was extracted with CH₂Cl₂ (3×50 mL) and the combinedorganic extracts were dried (MgSO₄), filtered and concentrated underreduced pressure. Purification by column chromatography on silica gel(CH₂Cl₂/MeOH, 80:1) afforded the desired nitrile (1.19 g, 36%) as anorange syrup. ¹H NMR (CDCl₃) δ −0.09 (s, 9H), 0.81-0.87 (m, 2H),1.56-1.75 (m, 2H), 1.87-2.07 (m, 2H), 2.01-2.26 (m, 1H), 2.29-2.53 (m,2H), 2.62-2.86 (m, 4H), 3.35-3.48 (m, 2H), 3.95-4.01 (m, 1H), 4.16 (d,1H, J=13.8 Hz), 4.26 (d, 1H, J=13.5 Hz), 5.76 (d, 1H, J=11.1 Hz), 6.17(d, 1H, J=11.0 Hz), 7.04 (dd, 1H, J=7.5, 4.5 Hz), 7.22-7.28 (m, 2H),7.32 (d, 1H, J=7.5 Hz), 7.43-7.46 (m, 1H), 7.69-7.73 (m, 1H), 8.46 (dd,1H, J=4.8, 1.3 Hz).

4-{(5,6,7,8-Tetrahydro-quinolin-8-yl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-ylmethyl]-amino}-butyronitrile(840 mg, 1.75 mmol) was dissolved in NH₃ saturated MeOH (15 mL), treatedwith Raney nickel (excess), and placed under 45 psi H₂ on a Parr shakerfor 16 hours. The mixture was diluted with MeOH and filtered throughCelite. The cake was washed with MeOH and the combined filtrate wasconcentrated under reduced pressure. Purification by columnchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 50:2:1) afforded thedesired amine (560 mg, 66%) as an orange syrup. ¹H NMR (CDCl₃) δ −0.10(s, 9H), 0.81 (t, 2H, J=9.0 Hz), 1.43-1.50 (m, 4H), 1.59-1.76 (m, 1H),1.86-2.09 (m, 2H), 2.08-2.23 (m, 1H), 2.56-2.71 (m, 4H), 2.76-2.85 (m,2H), 2.41 (t, 2H, J=8.1 Hz 4.07-4.12 (m, 3H), 5.71 (d, 1H, J=11.1 Hz),7.37 (d, 1H, J=11.1 Hz), 7.05 (dd, 1H, J=7.5, 4.5 Hz 7.21-7.29 (m, 2H),7.34 (d, 1H, J=6.6 Hz), 7.40-7.45 (m, 1H), 7.71-7.76 (m, 1H), 8.58 (d,1H, j=3.6 Hz).

Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine

Preparation of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine(Smith, J.; Liras, J. L.: Schneider, S. E.: Anslyn. E J. Org. Chem.1996, 61, 8811-8818)

To a solution of trans-1,4-cyclohexanediamine (8.01 g, 70.1 mmol) inCHCl₃ (230 mL) was added a solution of di-tert-butyl dicarbonate (7.67g, 35.1 mmol) in CHCl₃ (50 mL) via syringe pump over a period of 6hours. The resultant white suspension was stirred at room temperaturefor an additional 10 hours then concentrated in vacuo and diluted withCH₂Cl₂ (100 mL) and saturated aqueous Na₂CO₃ (100 mL). The layers wereseparated and the organic layer was washed saturated aqueous Na₂CO₃(2×30 mL). The combined organic phases were dried (Na₂SO₄), filtered andconcentrated to give the title compound (5.30 g, 71% based on Boc₂O) asa white solid.

Following General Procedure for Reductive Amination Using NaBH(OAc)₃: Toa stirred solution of 6,7-dihydro-5H-quinolin-8-one (3.04 g, 20.65 mmol)and N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine (4.42 g, 20.65mmol) in dry THF (100 mL) was added AcOH (3 mL) and NaBH(OAc)₃ (5.69 g,26.85 mmol) and the mixture stirred overnight at room temperature.Purification by column chromatography on silica gel(CH₂Cl_(2/)MeOH/NH₄OH, 96:4:0 then 94:5:1) afforded the desired amine(3.79 g, 53%) as a white solid.

Example 1 COMPOUND 1: Preparation of(1H-Benzimidazol-2-ylmethyl)-piperidin-3-ylmethyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt) Preparation of3-formyl-N-tert-butoxycarbonyl-piperidine

To a solution of 3-piperidinemethanol (0.544 g, 4.72 mmol) in THF (20mL) was added di-tert-butyl dicarbonate (1.01 g, 4.63 mmol) and themixture stirred at room temperature for 2 hours. The mixture wasconcentrated under reduced pressure and the resultant crude product wasused without further purification in the next reaction.

To a suspension of the alcohol from above (˜4.7 mmol) and powdered 3 Åmolecular sieves (1.17 g) in CH₂Cl₂ (10 mL) was added 4-methylmorpholineN-oxide (0.672 g, 5.74 mmol) and tetrapropylammonium perruthenate (0.084g, 0.24 mmol) and the mixture stirred overnight. The reaction wasconcentrated under reduced pressure and purified by columnchromatography through a plug of silica gel (ethyl acetate/hexanes, 1:2)to afford the title compound (0.429 g, 43% over 2 steps) as a clear oil.¹H NMR (CDCl₃) δ 1.46 (br s, 9H), 1.48-1.55 (m, 1H), 1.65-1.73 (m, 2H),1.91-1.99 (m, 1H), 2.40-2.44 (m, 1H), 3.04-3.13 (m, 1H), 3.32 (dd, 1H,J=15, 9 Hz), 3.60-3.65 (m, 1H), 3.89-3.94 (m, 1H), 9.70 (s, 1H).

Using General Procedure B: To a stirred solution of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(159 mg, 0.57 mmol) and 3-formyl-N-tert-butoxycarbonyl-piperidine (125mg, 0.59 mmol) in CH₂Cl₂ (5 mL) was added NaBH(OAc)₃ (157 mg, 0.74 mmol)and the resultant mixture was stirred at room temperature for 2.5 hours.Purification of the crude material by column chromatography on silicagel (CH₂Cl₂/MeOH, 96:4) afforded the alkylated product (185 mg, 68%) asa mixture of diastereomers.

The yellow foam from above (185 mg, 0.39 mmol) oil was dissolved inCH₂Cl₂/TFA (1:1, 2 mL) and the mixture stirred overnight. The reactionwas then concentrated and diluted with CH₂Cl₂ (30 mL) and 1 N NaOH (30mL). The aqueous layer was washed with CH₂Cl₂ (2×10 mL) and the combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated toafford the Boc-deprotected material as a mixture of diastereomers.Purification and separation of the diastereomers by radialchromatography on silica gel (1 mm plate, 50:1:1 CH₂Cl₂/MeOH/NH₄OH)afforded a top, less polar diastereomer (25 mg, 17%) and a bottom, morepolar one (20 mg, 14%), both as clear foams.

Using General Procedure D: Conversion of the more polar, bottomdiastereomer from above (20 mg, 0.05 mmol) to the hydrobromide saltfollowed by re-precipitation of the intermediate solid frommethanol/ether gave COMPOUND 1 (34 mg, 97%) as a white solid. ¹H NMR(D₂O) δ 0.97-1.09 (m, 1H), 1.44-1.57 (m, 1H), 1.72-1.88 (m, 2H),1.90-2.07 (m, 2H), 2.13-2.36 (m, 4H), 2.53 (br t, 1H, J=12 Hz),2.74-2.90 (m, 2H), 2.98-3.00 (m, 2H), 3.27-3.32 (m, 2H), 4.38 (d, 1HJ=16.5 Hz), 4.48 (d, 1H J=16.5 Hz), 4.50-4.55 (m, 1H), 7.62 (dd, 2H,J=6.3, 3.3 Hz), 7.81 (dd, 2H, J=6.3, 3.3 Hz), 7.89 (dd, 1H, J=7.8, 6Hz), 8.37 (d, 1H, J=8.1 Hz), 8.67 (d, 1H, J=5.6 Hz); ¹³C NMR (D₂O) δ19.89, 20.27, 21.58, 26.64, 27.79, 31.91, 44.57, 47.09, 48.00, 54.69,59.91, 114.34, 126.18, 127.09, 131.14, 139.59, 141.23, 148.32, 150.59,150.76. ES-MS m/z 376 (M+H). Anal. Calcd. for C₂₃H₂₉N₅.3.0HBr.2.2H₂O: C,41.99; H, 5.58; N, 10.65; Br, 36.44. Found: C, 42.05; H, 5.44; N, 10.50;Br, 36.40.

Example 2

COMPOUND 2: Preparation of(1H-Benzimidazol-2-ylmethyl)-piperidin-3-ylmethyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

Using General Procedure D: Conversion of the top, less polardiastereomer from above (see COMPOUND 1) (25 mg, 0.07 mmol) to thehydrobromide salt followed by re-precipitation of the intermediate solidfrom methanol/ether gave COMPOUND 2 (39 mg, 88%) as a white solid. ¹HNMR (D₂0) δ 1.07-1.19 (m, 1H), 1.54-1.68 (m, 1H), 1.74-1.90 (m, 3H),1.97-2.07 (m, 2H), 2.13-2.22 (m, 1H), 2.30-2.43 (m, 2H), 2.52 (br t, 1H,J=12 Hz), 2.80 (td, 1H, J=13.2, 2.4 Hz), 2.92 (dd, 1H, J=13.8, 4.5 Hz),2.98-3.00 (m, 2H), 3.32-3.36 (m, 1H), 3.61-3.65 (m, 1H), 4.38 (d, 1HJ=16.5 Hz), 4.46 (d, 1H J=16.5 Hz), 4.52 (dd, 1H, J=10.5, 5.7 Hz), 7.63(dd, 2H, J=6.3, 3.3 Hz), 7.82 (dd, 2H, J=6.3, 3.3 Hz), 7.90 (dd, 1H,J=7.5, 6.3 Hz), 8.37 (d, 1H, J=7.8 Hz), 8.68 (d, 1H, J=6 Hz); ¹³C NMR(D₂O) δ 18.97, 19.39, 21.05, 26.03, 26.91, 31.14, 43.69, 46.67, 47.04,54.41, 58.71, 113.46, 125.31, 126.27, 130.15, 138.77, 140.30, 147.54,149.50, 149.74. ES-MS m/z 376 (M+H). Anal. Calcd. forC₂₃H₂₉N₅.3.0HBr.2.6H₂O: C, 41.54; H, 5.64; N, 10.53; Br, 36.04. Found:C, 41.47; H, 5.41; N, 10.22; Br, 36.19.

Example 3

COMPOUND 3: Preparation of(1H-Benzimidazol-2-ylmethyl)-piperidin-2-ylmethyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt) Preparation of 2-formyl-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 2-piperidinemethanol (561 mg, 4.9mmol) in dry THF (10mL) was added di-tert-butyl dicarbonate (1.14 g, 5.2 mmol) and themixture stirred overnight at room temperature. The reaction mixture wasconcentrated in vacuo to afford a colourless oil which was used in thenext step without any further purification.

To a stirred solution of 2-hydroxymethyl-piperidine-1-carboxylic acidtert-butyl ester (0.737 g, 3.4 mmol) in dry CH₂Cl₂ (10 mL) was added 3 Åmolecular sieves (1.03 g), N-methylmorpholine N-oxide (0.644 g, 5.5mmol), and tetrapropylammonium perruthenate (72 mg, 0.21 mmol) and themixture stirred at room temperature for 3 h. The reaction mixture waspurified through a silica gel plug (Hexanes/EtOAc, 70:30 followed by100:0) to afford the title aldehyde (0.500 g, 70%) as a pale yellow oil.

Using General Procedure B: To a stirred solution of2-formyl-piperidine-1-carboxylic acid tert-butyl ester (0.163 g, 0.76mmol) in dry CH₂Cl₂ (3.5 mL) was added(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.210 g, 0.76 mmol) and sodium triacetoxyborohydride (0.240 g, 1.1mmol) and the mixture stirred overnight at room temperature.Purification by column chromatography on silica gel (CH₂Cl₂/MeOH, 98:2followed by 96:4) gave a pale yellow foam containing a mixture ofdiastereomers (0.305 g).

To a stirred solution of the diastereomers (0.305 g) in dry CH₂Cl₂ (2mL) was added trifluoroacetic acid (1 mL) dropwise and the mixturestirred at room temperature for 3.5 h. The reaction mixture was dilutedwith CH₂Cl₂ (10 mL) and then concentrated in vacuo. The concentrate wasdiluted with CH₂Cl₂ (20 mL) and extracted with 1N NaOH (30 mL). Theaqueous layer was washed with CH₂Cl₂ (2×15 mL) and then the combinedorganic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo.Purification and separation of the two diastereomers by radialchromatography on a 1 mm TLC grade silica gel plate (CH₂Cl₂/MeOH/NH₄OH,100:1:1 followed by 50:1:1) afforded a less polar diastereomer (63 mg,22%) and a more polar one (22 mg, 8%) (stereochemistry unknown), both ascolourless oils.

Using General Procedure D: Conversion of the less polar distereomer fromabove (63 mg, 0.17 mmol) to the hydrobromide salt gave COMPOUND 3 (83mg) as a white solid. ¹H NMR (D₂O) δ 1.34-1.68 (m, 3H), 1.73-1.93 (m,3H), 1.93-2.08 (m, 2H), 2.08-2.23 (m, 1H), 2.24-2.38 (m, 1H), 2.79 (dd,1H, J=14.7, 9.9 Hz), 2.94-3.07 (m, 3H), 3.27 (dd, 1H, J=14.7, 9.9 Hz),3.38-3.56 (m, 2H), 4.33 (s, 2H), 4.57 (dd, 1H, J=9.9, 5.7 Hz), 7.56-7.62(m, 2H), 7.70-7.83 (m, 3H), 8.28 (d, 1H, J=7.8 Hz), 8.57 (d, 1H, J=4.8Hz); ¹³C NMR (D₂O) δ 19.84, 20.28, 21.76, 22.16, 26.99, 27.83, 45.34,47.01, 54.30, 54.82, 58.86, 114.55, 125.99, 127.08, 131.59, 140.23,141.046, 147.96, 149.03, 149.84; ES-MS m/z 376 (M+H); Anal. Calcd. forC₂₃H₂₉N₅.3.0HBr.1.2H₂O.0.3C₄H,₁₀O: C, 43.90; H, 5.69; N, 10.58; Br,36.20. Found: C, 43.78; H, 5.47; N, 10.54; Br, 36.41.

Example 4

COMPOUND 4: Preparation of(1H-Benzimidazol-2-ylmethyl)-piperidin-2-ylmethyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

Using General Procedure D: Conversion of the more polar distereomer fromabove (see COMPOUND 3) (22 mg, 0.059 mmol) to the hydrobromide salt gaveCOMPOUND 4 (35 mg) as a white solid. ¹H NMR (D₂O) δ 1.22-1.39 (m, 1H),1.39-1.68 (m, 2H), 1.71-1.93 (m, 3H), 2.03-2.24 (m, 3H), 2.31-2.42 (m,1H), 2.79-2.89 (m, 1H), 2.91-3.07 (m, 3H), 3.16 (dd, 1H, J=13.8, 6.0Hz), 3.32-3.49 (m, 2H), 4.34 (d, 1H, J=15.9 Hz), 4.43 (d, 1H, J=16.2Hz), 4.53 (dd, 1H, J=10.2, 6.0 Hz), 7.54-7.61 (m, 2H), 7.65-7.77 (m,3H), 8.25 (d, 1H, J=7.8 Hz), 8.49 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ20.04, 20.25, 21.54, 22.23, 27.04, 27.75, 45.22, 46.43, 54.61, 55.98,60.69, 114.46, 125.90, 127.01, 131.66, 139.70, 140.96, 148.03, 149.70;ES-MS m/z 376 (M+H); Anal. Calcd. for C₂₃H₂₉N₅.3.0HBr.2.2H₂O: C, 41.99;H, 5.58; N, 10.56; Br 36.44. Found: C, 42.22; H, 5.46; N, 10.47; Br,36.23.

Example 5

COMPOUND 5: Preparation of(1H-Benzimidazol-2-ylmethyl)-(S)-1-pyrrolidin-2-ylmethyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

Using General Procedure B: To a stirred solution of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(148 mg, 0.53 mmol) and N-tert-butoxycarbonyl-L-prolinal (110 mg, 0.55mmol) in CH₂Cl₂ (5 mL) was added NaBH(OAc)₃ (146 mg, 0.69 mmol) and theresultant mixture was stirred at room temperature overnight.Purification of the crude material by radial chromatography on silicagel gel (2 mm plate, 50:1:1 CH₂Cl₂/MeOH/NH₄OH then 10:1:1CH₂Cl₂/MeOH/NH₄OH) afforded the desired amine (73 mg, 30%) as a yellowoil.

Using General Procedure D: Conversion of the oil from above (40 mg, 0.11mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 5 (53 mg, 73%) as abeige solid. ¹H NMR (D₂O) δ 1.22-1.28 (m, 1H), 1.61-1.74 (m, 1H),1.75-1.89 (m, 1H), 1.99-2.09 (m, 3H), 2.16-2.31 (m,1H), 2.33-2.39 (m,1H), 2.92 (dd, 1H, J=14.4, 9.3 Hz), 2.97-3.03 (m, 1H), 3.25 (q, 1H,J=7.2 Hz), 3.33-3.41 (m, 1H), 3.35 (td, 2H, J=7.5, 2.4 Hz), 3.86-3.96(m, 1H), 4.34 (d, 1H, J=16.2 Hz), 4.42 (d, 1H, J=16.2 Hz), 4.59 (dd, 1H,J=10.2, 6 Hz), 7.59 (dd, 2H, J=6.3, 3.3 Hz), 7.78 (dd, 2H, J=6.3, 3.3Hz), 7.79-7.83 (m, 1H), 8.31 (d, 1H, J=8.7 Hz), 8.60 (d, 1H, J=5.1 Hz);¹³C NMR (D₂O) δ 19.91, 20.29, 22.88, 27.80, 28.46, 45.88, 47.28, 52.97,58.23, 58.77, 114.47, 126.02, 127.00, 131.50, 140.22, 141.00, 147.99,149.62, 149.98. ES-MS m/z 362 (M+H). Anal. Calcd. forC₂₂H₂₇N₅.3HBr.2H₂O.0.2C₄H₁₀O: C, 41.80; H, 5.54; N, 10.69; Br, 36.59.Found C, 41.66; H, 5.45; N, 10.65; Br, 36.93.

Example 6

COMPOUND 6: Preparation of(1H-Benzimidazol-2-ylmethyl)-piperidin-4-ylmethyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt) Preparation of1-(tert-butoxycarbonyl)-piperidine-4-carboxaldehyde

To a solution of ethyl isonipecotate (0.750 g, 4.77 mmol) in THF (24 mL)was added water (1 mL) followed by di-tert-butyl dicarbonate (1.09 g,5.00 mmol) and the resultant mixture was stirred at room temperature forone hour. The mixture was diluted with ethyl acetate (50 mL) and theorganic phase was washed with brine (3×20 mL), dried (MgSO₄), andconcentrated to provide 1.20 g (98%) of1-(tert-butoxycarbonyl)-4-(carboethoxy)-piperidine as a colorless oil.

To a cold (−78° C.), stirred solution of the oil from above (1.20 g,4.67 mmol) in dry THF (46 mL) was added diisobutylaluminum hydride (1.0M in THF, 15 mL, 15 mmol). After 30 minutes, the reaction mixture waswarmed to room temperature and stirred for an additional 20 minutes.Saturated aqueous NH₄Cl (5 mL) was added and the resultant white slurrywas stirred at room temperature for 45 minutes. Solid MgSO₄ (5 g) wasadded and the mixture was filtered through Florisil.® The column waswashed with ethyl acetate (200 mL). The combined eluant was concentratedunder reduced pressure to provide 1.01 g (97%) of1-(tert-butoxycarbonyl)-4-(hydroxymethyl)-piperidine as a white solid.

To a solution of the above alcohol (0.437 g, 2.03 mmol) in CH₂Cl₂ (10mL), at room temperature, was added sequentially 3 Å molecular sieves(1.07 g), N-methylmorpholine N-oxide (0.365 g, 3.11 mmol), andtetrapropylammonium perruthenate (70 mg, 0.20 mmol). After 1 hour, themixture was filtered through a short column of silica gel and the cakewas washed with ethyl acetate. The solvent was removed from the filtrateunder reduced pressure. Purification of the crude material by columnchromatography on silica gel (4:1 hexanes-ethyl acetate) provided 90 mg(20%) of 1-(tert-butoxycarbonyl)-piperidine-4-carboxaldehyde as acolorless oil. ¹H NMR (CDCl₃) δ 1.46 (s, 9H), 1.51-1.62 (m, 2H),1.85-1.93 (m, 2H), 2.37-2.46 (m, 1H), 2.88-2.97 (m, 2H), 3.94-4.00 (m,2H), 9.66 (s, 1H).

Using General Procedure B: Reaction of1-(tert-butoxycarbonyl)-piperidine-4-carboxaldehyde (0.090 g, 0.42 mmol)and(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.110 g, 0.40 mmol) with NaBH(OAc)₃ (0.223g, 1.05 mmol) in CH₂Cl₂ (5mL) for 20 h followed by purification of the crude material by columnchromatography on silica gel (50:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided 0.120g (63%) of an off-white solid.

Using General Procedure D: Conversion of the off-white solid (120 mg) tothe hydrobromide salt with simultaneous removal of the BOC-protectinggroup, followed by re-precipitation of the intermediate solid frommethanol/ether, gave COMPOUND 6 (98 mg) as a white solid. ¹H NMR (D₂O) δ1.13-1.28 (m, 2H), 1.80-2.36 (m, 8H), 2.81-3.00 (m, 5H), 3.35-3.43 (m,2H), 4.38 (d, 1H, J=16.5 Hz), 4.46 (d, 1H, J=16.5 Hz), 4.52 (dd, 1H,J=10.5, 6.0 Hz), 7.59-7.65 (m, 2H), 7.78-7.85 (m, 2H), 7.89 (dd, 1H,J=7.8, 6.0 Hz), 8.37 (d, 1H, J=8.1 Hz), 8.67 (d, 1H, J=5.7 Hz); ¹³C NMR(D₂O) δ 17.72, 18.24, 24.98 (2 carbons), 25.71, 29.64, 41.94, 42.05,45.79, 54.96, 57.53, 112.25, 124.08, 125.04, 128.97, 137.47, 139.09,146.24, 148.75 (2 carbons); ES-MS m/z 376 (M+H). Anal. Calcd. forC₂₃H₂₉N₅.3.1HBr.1.8H₂O: C, 41.93; H, 5.46; N, 10.63; Br, 37.60. Found:C, 42.07; H, 5.55; N, 10.28; Br, 37.43.

Example 7

COMPOUND 7:(1H-Benzimidazol-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt) Preparation of4-(5,6,7,8-Tetrahydro-guinolin-8-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

Using general procedure B: Reaction of Boc-4-piperidone (641 mg, 3.22mmol 5,6,7,8-Tetrahydro-quinolin-8-ylamine (476 mg, 3.22 mmol), sodiumtriacetoxyborohydride (1.36 g, 6.44 mmol) and acetic acid (0.25 mL) inTHF (25mL) at room temperature under N₂ for 20 min afforded the titlecompound (1.05 g, 98%) as a yellow oil.

The 4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-piperidine- 1-carboxylicacid tert-butyl ester (240 mg, 0.72 mmol),2-Chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (212 mg,0.79 mmol), DIPEA (0.20 mL, 1.58 mmol), and KI (6 mg, 0.036 mmol) wereheated to 60° C. in CH₃CN (7 mL) overnight under N₂. The reactionmixture was concentrated in vacuo, diluted with ethyl acetate, washedwith NH₄Cl (aq), NaCl (aq), and dried (MgSO₄). Evaporation of thesolvent and purification of the residue by flash chromatography onsilica gel (CH₂Cl₂—MeOH—NH₄OH 98:1:1) afforded the title compound (331mg, 82%) as a white foam.

Using General Procedure D: Conversion of the foam from above (100 mg,0.18 mmol) to the hydrobromide salt using an acetic acid/HBr solution,followed by re-precipitation of the salt from diethyl ether gaveCOMPOUND 7 as a white solid. ¹H NMR (CD₃OD) mixture of isomers δ1.94-2.15 (m, 3H), 2.19-2.26 (m, 2H), 2.41-2.51 (m, 2H), 2.60-2.65 (m,1H), 3.03-3.14 (m, 4H), 3.18-3.28 (m, 1H), 3.41-3.52 (m, 2H), 4.61 (d,2H, J=3.9 Hz), 4.67-4.72 (m, 1H), 7.58-7.63 (m, 2H), 7.86-7.94 (m, 3H),8.37 (d, 1H, J=8.1 Hz), 8.91 (d, 1H, J=5.7 Hz); ¹³C NMR (CD₃OD) mixtureof isomers δ 25.71, 29.19, 31.67, 32.47, 33.30, 48.62, 48.76, 48.93,60.93, 63.27, 118.96, 130.51, 131.51, 136.12, 144.91, 145.36, 152.51,156.45, 156.63; ES-MS m/z 362.3 (M+H); Anal. Calcd. For(C₂₂H₂₇N₅).3.0(HBr).1.8 (H2O).0.4(C₄H₁₀O): C, 42.54; H, 5.69; N, 10.51;Br, 35.98. Found C, C, 42.61; H, 5.47; N, 10.46; Br, 35.93

Example 8

COMPOUND 8: Preparation of(1H-benzimidazol-2-ylmethyl)-piperidin-3-yl-(5,6.7.8-tetrahydroguinolin-8-yl)amine(hydrobromide salt) Preparation oftert-butyl3-hydroxy-1-piperidinecarboxylate

To a 0° C. solution of 3-hydroxypiperidine (2.12 g, 21.0 mmol) in EtOH(20 mL) was added NEt₃ (5.6 mL, 40.2 mmol), followed by a solution of(Boc)₂O (5.03 g, 23.0 mmol) in EtOH (20 mL). The reaction stirred atroom temperature for one hour, and then the solvent was evaporated underreduced pressure. The residue was dissolved in EtOAc (50 mL) and washedwith 10% citric acid (50 mL), water (50 mL) and brine (50 mL). Theorganic solution was dried (MgSO₄), filtered and evaporated underreduced pressure to afford the crude product as a white solid (3.55 g,17.6 mmol, 84%). ¹H NMR (CDCl₃) δ 1.45 (s, 9H), 1.48-1.52 (m, 2H),1.72-1.78 (m, 1H), 1.84-1.94 (m, 1H), 2.12 (br. s, 1H), 3.01-3.12 (m,2H), 3.46-3.59 (m, 1H), 3.65-3.78 (m, 2H).

Preparation of tert-butyl 3-oxo-1-piperidinecarboxylate

To a 0° C. solution of the alcohol (2.01 g, 10.0 mmol) in CH₂Cl₂ (50 mL)was added crushed 3 Å molecular sieves (5.26 g),4-methylmorpholine-N-oxide (1.76 g, 15.0 mmol) and tetrapropylammoniumperruthenate (357 mg, 1.02 mmol). The resulting black solution wasstirred at 0° C. for 20 minutes, then at room temperature for a furtherone hour. The mixture was filtered through a plug of silica, rinsed withEtOAc and the concentrated filtrate was purified by flash chromatographyon silica gel (EtOAc/hexane, 1:1) to afford the ketone as a yellowliquid (1.49 g, 7.48 mmol, 75%). ¹H NMR (CDCl₃) δ 1.46 (s, 9H), 1.98(ddd, 2H, J=12.3, 6.5, 6.0 Hz), 2.47 (t, 2H, J=6.5 Hz), 3.58 (t, 2H,J=6.0 Hz), 4.00 (s, 2H).

Preparation of tert-butyl3-(5,6,7,8-tetrahydroquinolin-8-ylamino)-piperidine-1-carboxylate

To a solution of 8-amino-5,6,7,8-tetrahydroquinoline (1.00 g, 6.75 mmol)in MeOH (30 mL) was added a solution of the ketone (1.40 g, 7.03 mmol)in MeOH (20 mL). The reaction stirred at room temperature for 16 hours.NaBH4 (848 mg, 22.4 mmol) was added and the mixture stirred for afurther 45 minutes. The solvent was evaporated under reduced pressure,and the residue was taken up into CH₂Cl₂ (50 mL) and washed withsaturated aqueous NaHCO₃ (10 mL) and brine (10 mL). The organic solutionwas dried (MgSO₄), filtered and evaporated under reduced pressure.Purification by flash column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 9:1:0.5) gave a brown oil which, following a secondpurification (CH₂Cl₂/MeOH, 97:3) afforded the amine as a yellow oil (638mg, 1.92 mmol, 28%). ¹H NMR (CDCl₃) δ 1.22-1.40 (m, 2H), 1.47 (s, 9H),1.65-1.81 (m, 3H), 1.91-2.04 (m, 2H), 2.11-2.25 (m, 2H), 2.44-2.65 (m,1H), 2.65-2.90 (m, 4H), 3.88-4.05 (m, 2H), 4.05-4.31 (m,1H), 7.06 (dd,1H, J=7.7, 4.7 Hz), 7.36 (d, 1H, J=7.8 Hz), 8.37 (d, 1H, J=4.3 Hz).

Preparation of COMPOUND 8:

A mixture of this amine (247 mg, 0.75 mmol), tert-butyl2-chloromethyl-benzimidazole-1-carboxylate (238 mg, 0.89 mmol), DIPEA(0.20 mL, 1.2 mmol) and KI (14 mg, 0.08 mmol) in CH₃CN (4 mL) was heatedat 60° C. for 20 hours. After cooling, the reaction was diluted withsaturated aqueous NaHCO₃ (10 mL) and extracted with CH₂Cl₂ (25 mL×3).The organic solution was dried (MgSO₄), filtered and evaporated underreduced pressure. The resulting dark red oil was purified by flashcolumn chromatography on silica gel (CH₂Cl₂/MeOH, 9:1) giving an orangefoam. A second purification (CH₂Cl₂/MeOH, 19:1) gave the tertiary amineas an orange solid (83 mg, 20%).

This material was stirred in TFA (1.5 mL) at room temperature for 2hours, and then the excess solvent was evaporated under reducedpressure. The residue was taken up into CH₂Cl₂ (20 mL) and washed withsaturated aqueous NaHCO₃ (10 mL). The aqueous solution was extractedwith CH₂Cl₂ (20 mL×2) and the combined organic extracts were dried(MgSO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,89:10:1) gave an approximately 2:1 mixture of diastereomers of the freeamine as a yellow foam (21 mg, 0.06 mmol, 41%).

To a solution of this material (20 mg, 0.055 mmol) in glacial HOAc (1mL) was added a saturated HBr in HOAc solution (0.5 mL). The reactionstirred at room temperature for 40 minutes. Et₂O (2 mL) was added, thesuspension was stirred and the solvent was decanted. The precipitate waswashed with Et₂O (1 mL×5), then dried under reduced pressure givingCOMPOUND 8 as a yellow solid (26 mg, 0.038 mmol, 70%). ¹H NMR (D₂O) δ1.61-1.94 (m, 3H), 1.98-2.11 (m, 1H), 2.11-2.17 (m, 2H), 2.17-2.49 (m,1H), 2.80-2.92 (m, 1H), 2.93-3.01 (m, 2H), 3.09-3.25 (m, 2H), 3.31-3.40(m, 1H), 3.82-3.90 (m, 1H), 4.43 (d, 1H, J=16.5 Hz), 4.55 (d, 1H, J=16.5Hz), 4.55-4.65 (m, 1H), 7.53-7.60 (m, 2H), 7.67-7.77 (m, 3H), 8.20 (d,0.67H, J=7.8 Hz), 8.23 (d, 0.33H, J=7.8 Hz), 8.51 (d, 0.67H, J=5.7 Hz),8.55 (d, 0.33H, J=5.7 Hz). ¹³C NMR (D₂O) δ 20.5 and 20.6, 21.9 and 22.1,24.2 and 24.5, 26.8 and 27.5, 28.0, 43.2, 44.0, 46.2 and 47.0, 58.5 and59.2, 114.4, 125.8, 126.8, 131.7, 139.5, 140.5 and 141.6, 147.7 and147.8, 150.6 and 151.2. ES-MS m/z 362 (M+H). Anal. Calcd. forC₂₂H₂₇N₅.3.1HBr.1.8H₂O.0.3C₄H₁₀O: C, 41.78; H, 5.55; N, 10.50; Br,37.14. Found C, 41.48: H, 5.44; N, 10.44; Br, 37.50.

Example 9

COMPOUND 9: Preparation of(1H-benzimidazol-2-ylmethyl)-piperidin-3-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amine(hydrobromide salt)

The free base was prepared by N-alkylation and TFA deprotection, asdescribed previously (see COMPOUND 8). The crude material was purifiedby flash column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,9:1:0.1) giving 18 mg of a single diastereomer (0.05 mmol, 5%) as abrown foam, along with 51 mg of the mixture of diastereomers (0.14 mmol,14%) as a yellow foam.

The single diastereomer (18 mg, 0.05 mmol) was dissolved into HOAc (1mL) and saturated HBr in HOAc (0.5 mL) was added. The solution stirredat room temperature for 40 minutes. Et₂O (2 mL) was added, the mixturewas stirred and the solvent was decanted. The precipitate was washedwith Et₂O (1 mL×5) and dried under reduced pressure at 90° C., givingthe diastereomer COMPOUND 9 as a yellow powder (22 mg, 0.03 mmol, 67%).¹H NMR (D₂O) δ 1.57-1.74 (m, 1H), 1.75-1.90 (m, 2H), 2.03-2.12 (m, 1H),2.12-2.24 (m, 2H), 2.31-2.47 (m, 2H), 2.80-2.92 (m, 1H), 2.92-3.00 (m,2H), 3.06-3.20 (m, 2H), 3.29-3.38 (m, 1H), 3.47-3.57 (m, 1H), 4.43-4.53(m, 1H), 4.48 (d, 1H, J=16.4 Hz), 4.57 (d, 1H, J=16.4 Hz), 7.51-7.58 (m,2H), 7.68-7.76 (m, 3H), 8.20 (d, 1H, J=7.5 Hz), 8.53 (d, 1H, J=5.7 Hz).^(—NMR (D) ₂O) δ 20.5, 21.9, 24.2, 26.8, 27.5, 43.4, 43.9, 47.0, 55.5,59.2, 114.4, 125.8, 126.6, 132.0, 139.7, 140.5, 147.6, 150.9, 151.1.ES-MS m/z362 (M+H). Anal. Calcd. for C₂₂H₂₇N₅.3.0HBr.1.8 H₂O.0.3C₄H₁₀O:C, 42.29; H, 5.60; N, 10.63; Br, 36.38. Found: C, 42.27; H, 5.60; N,10.62; Br, 36.42.

Example 10

COMPOUND 10: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine(hydrobromide salt)

Using General Procedure B: Reaction ofN-(tert-butoxycarbonyl)-2-amino-acetaldehyde (0.112 g, 0.71 mmol) and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.189 g, 0.50 mmol) with NaBH(OAc)₃ (0.215 g, 1.01 mmol) in CH₂Cl₂ (5mL) for 18 h followed by purification of the crude material by radialchromatography on silica gel (2 mm plate, 100:1:1 CH₂Cl₂—CH₃OH—NH₄OH)provided a white solid (0.167 g, 64%).

Using General Procedure D: Conversion of the white solid (167 mg) to thehydrobromide salt with simultaneous removal of the BOC-protectinggroups, followed by re-precipitation of the intermediate solid frommethanol/ether, gave COMPOUND 10 (173 mg) as a white solid. ¹H NMR (D₂O)δ 1.75-1.89 (m, 1H), 1.98-2.11 (m, 1H), 2.15-2.22 (m, 1H) 2.38-2.43 (m,1H), 2.91-3.02 (m, 3H), 3.16-3.31 (m, 3H), 4.40 (d, 1H, J=16.5 Hz),4.52-4.67 (m, 2H), 7.58-7.63 (m, 2H), 7.76-7.84 (m, 3H), 8.32 (d, 1H,J=7.8 Hz), 8.59 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 20.30, 20.44, 27.68,37.75, 47.12, 49.11, 60.07, 114.40, 126.08, 127.11, 131.17, 139.78,140.92, 148.23, 150.09, 150.17; ES-MS m/z 322 (M+H). Anal. Calcd. forC₁₉H₂₃N₅.3.0HBr.1.1H₂O: C, 39.08; H, 4.87; N, 11.99; Br, 41.05. Found:C, 39.19; H, 4.98; N, 11.76; Br, 40.89.

Example 11

COMPOUND 11: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N²-(5-nitro-pyridin-2-yl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine(hydrobromide salt)

Using General Procedure B: To a solution of6,7-dihydro-5H-quinolin-8-one (294 mg, 2 mmol) in MeOH (6 mL) was added2-(2-aminoethylamino)-5-nitropyridine (368 mg, 2.02 mmol) and theresultant solution was stirred at room temperature for 3 hours. SolidNaBH₄ (168 mg, 4.44 mmol) was added to the solution and the mixture wasstirred at room temperature for an additional 45 minutes. The resultantcrude yellow foam (639 mg) was used without further purification in thenext step.

Using the General procedure for N-alkylation: To a solution of thematerial from above (639 mg), potassium iodide (5 mg, 0.030 mmol) andN,N-diisopropylethylamine (0.70 mL, 4.0 mmol) in CH₃CN (10 mL) was addedN-(tert-butoxycarbonyl)-2-chloromethylbenzimidazole (prepared asdescribed by An, H.; Wang, T.; Mohan, V.; Griffey, R. H.; Cook, P. DTetrahedron 1998, 54, 3999-4012) (527 mg, 1.98 mmol) and the reactionstirred at 60° C. for 6.5 h. Purification of the crude brown foam byflash chromatography on silica gel (99:1 CH₂Cl₂/MeOH then 98:2 ) gavethe alkylated product,2-{[[2-(5-Nitro-pyridin-2-ylamino)-ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester, (645 mg, 60%) as a yellow foam.

Using General Procedure D: Conversion of the free base from above (84mg, 0.16 mmol) to the hydrobromide salt, followed by re-precipitation ofthe intermediate solid from methanol/ether, gave COMPOUND 11 (87 mg,78%) as a yellow solid. ¹H NMR (D₂O) δ 1.81-1.88 (m, 1H), 2.06-2.17 (m,2H), 2.38-2.43 (m, 1H), 2.88-2.96 (m, 1H), 3.01-3.03 (m, 2H), 3.14-3.21(m, 1H), 3.39-3.57 (m, 2H), 4.37 (d, 1H, J=16.8 Hz), 4.57 (d, 1H, J=16.8Hz), 4.61-4.66 (m, 1H), 6.49 (d, 1H, J=9.6 Hz), 7.42 (dd, 2H, J=6, 3Hz), 7.57 (dd, 2H, J=6, 3 Hz), 7.86-7.93 (m, 2H), 8.33 (br s, 1H), 8.37(d, 1H, J=7.8 Hz), 8.70 (d, 1H, J=6.6 Hz); ¹³C NMR (D₂O) δ 20.41, 20.79,27.80, 41.02, 49.30, 50.55, 62.07, 110.03, 110.77, 114.22, 126.02,126.66, 130.60, 133.75, 135.36, 139.77, 140.95, 143.67, 148.28, 150.42,151.28, 179.57; ES-MS m/z 444 (M+H). Anal. Calcd. forC₂₄H₂₅N₇O₂.2.9HBr.2.4H₂O: C, 39.96; H, 4.57; N, 13.59; Br, 32.12. Found:C, 40.17; H, 4.47; N, 13.20; Br, 32.03.

Example 12

COMPOUND 12: Preparation of(1H-benzimidazol-2-ylmethyl)-(2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-aminePreparation of toluene-4-sulfonic acid 2-tert-butoxycarbonylamino-ethylester

Tosyl chloride (1.50 g, 7.87 mmol) was added to a solution of(2-hydroxy-ethyl)-carbamic acid tert-butyl ester (0.84 g, 5.2 mmol) andEt₃N (1.23 mL, 8.82 mmol) in CH₂Cl₂ (26 mL), and the solution wasstirred at room temperature for 17 h. The solution was washed with H₂O(15 mL), and the aqueous phase was extracted with CH₂Cl₂ (10 mL). Thecombined organic phases were dried (MgSO₄) and concentrated in vacuo.Purification of the crude material by column chromatography on silicagel (20% EtOAc/hexanes) gave yellow crystals (1.29 g, 79%). ¹H NMR(CDCl₃) δ 1.41 (s, 9H), 2.45 (s, 3H), 3.38 (m, 2H), 4.07 (m, 2H), 4.82(br s, 1H), 7.35 (d, 2H, J=8.1 Hz), 7.79 (d, 2H, J=8.1 Hz).

(2-Imidazol-1-yl-ethyl)-carbamic acid tert-butyl ester

A solution of imidazole (253 mg, 3.72 mmol) in DMF (2 mL) was added to asuspension of NaH (60% in mineral oil, 164 mg, 4.10 mmol) in DMF (8 mL),and the mixture was stirred at room temperature for 45 minutes. Asolution of toluene-4-sulfonic acid 2-tert-butoxycarbonylamino-ethylester (1.29 g, 4.09 mmol) in DMF (6 mL) was added, and the mixture wasstirred at room temperature for 16 h then concentrated in vacuo. Theresidue was partitioned between H₂O (25 mL) and EtOAc (25 mL), and theaqueous phase was extracted with EtOAc (25 mL). The combined organicphases were dried (MgSO₄) and concentrated in vacuo. Purification of thecrude material by column chromatography on silica gel (200:5:1-100:5:1CH₂Cl₂/MeOH/NH₄OH) gave a colourless oil (224 mg, 29%). ¹H NMR (CDCl₃) δ1.44 (s, 9H), 3.43 (m, 2H), 4.08 (m, 2H), 4.64 (br s, 1H), 6.92 (s, 1H),7.09 (s, 1H), 7.46 (s, 1H).

(2-Imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

A solution of (2-imidazol-1-yl-ethyl)-carbamic acid tert-butyl ester(224 mg, 1.06 mmol) in 1:1 TFA/CH₂Cl₂ (4 mL) was stirred at roomtemperature for 1 h then concentrated in vacuo. The residue wasdissolved in 1 N NaOH(aq) (10 mL) then saturated with sodium chlorideand extracted with CHCl₃ (5×15 mL). The combined organic extracts weredried (MgSO₄) and concentrated in vacuo to give a yellow oil (55 mg).

Using General Procedure B: To a stirred solution of the amine from above(55 mg), 6,7-dihydro-5H-quinolin-8-one (73 mg, 0.50 mmol), and AcOH(0.030 mL, 0.52 mmol) in THF (5 mL) was added NaBH(OAc)₃ (315 mg, 1.49mmol) and the mixture was stirred at room temperature for 2 h. The crudematerial was dissolved in saturated HBr/AcOH (2 mL) and stirred at roomtemperature for 15 minutes. The solution was made basic with 10 NNaOH(aq) and extracted with CH₂Cl₂ (3×15 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. Purification ofthe crude material by column chromatography on silica gel (200:5:1CH₂Cl₂/MeOH/NH₄OH) gave a yellow oil (92 mg, 77%). ¹H NMR (CDCl₃) δ 1.73(m, 2H), 1.91-2.13 (m, 2H), 2.76 (m, 2H), 3.12 (m, 2H), 3.78 (m, 1H),4.11 (m, 2H), 7.01 (s, 1H), 7.08 (m, 2H), 7.38 (d, 1H, J=7.5 Hz), 7.56(s, 1H), 8.37 (d, 1H, J=3.9 Hz).

2-{[(2-Imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester

A mixture of(2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (92 mg,0.37 mmol), 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butylester (101 mg, 0.379 mmol), potassium iodide (3 mg, 0.02 mmol), andN,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in acetonitrile (4 mL)was heated at 60° C. for 15 h. Saturated NaHCO₃(aq) (15 mL) was added,and the mixture was extracted with CH₂Cl₂ (3×15 mL). The combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo.Purification of the crude material by column chromatography on silicagel (250:5:1 CH₂Cl₂/MeOH/NH₄OH) gave a yellow oil (21 mg, 12%). ¹H NMR(CDCl₃) δ 1.45 (m, 1H), 1.66 (m, 10H), 1.91 (m, 2H), 2.69 (m, 2H), 2.92(m, 1H), 3.18 (m, 1H), 3.67 (m, 2H), 4.20 (dd, 1H, J=10, 5.6 Hz), 4.67(d, 1H, J=15 Hz), 4.80 (d, 1H, J=15 Hz), 6.74 (s, 1H), 6.90 (s, 1H),7.01 (dd, 1H, J=7.7, 4.7 Hz), 7.73 (m, 1H), 7.86 (m, 1H), 8.38 (d, 1H,J=3.3 Hz).

(1H-Benzimidazol-2-ylmethyl)-(2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(COMPOUND 12)

A solution of2-{[(2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (21 mg, 0.044 mmol) in 3:1 TFA/CH₂Cl₂ (4 mL) wasstirred at room temperature for 30 minutes then concentrated in vacuo.The residue was partitioned between CH₂Cl₂ (20 mL) and 1 N NaOH(aq) (10mL), and the aqueous phase was extracted with CH₂Cl₂ (10 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuoto afford COMPOUND 12 as a yellow foam (15 mg, 83%). ¹H NMR (CDCl₃) δ1.73 (m, 2H), 1.99 (m, 1H), 2.20 (m, 1H), 2.69-2.88 (m, 2H), 2.92-3.08(m, 2H), 3.82-3.98 (m, 2H), 4.04 (d, 1H, J=17 Hz), 4.09 (m, 1H), 4.19(d, 1H, J=17 Hz), 6.70 (s, 1H), 6.93 (s, 1H), 7.18 (m, 3H), 7.42 (m,2H), 7.57 (br s, 2H), 8.51 (d, 1H, J=3.9 Hz); ¹³C NMR (CDCl₃) δ 21.55,25.06, 29.36, 46.03, 50.34, 52.23, 62.59, 119.32, 122.26, 122.82,129.55, 134.97, 137.93, 147.26, 155.42, 156.77. ES-MS m/z 373 (M+H).Anal. Calcd. for C₂₂H₂₄N₆.0.2CH₂Cl₂.0.8CH₄O: C, 66.55; H, 6.70; N,20.25. Found: C, 66.64; H, 6.40; N, 20.06.

Example 13

COMPOUND 13: Preparation of(1H-benzimidazol-2-ylmethyl)-[3-(1H-imidazol-2-yl)-propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-aminePreparation of 1-trityl-1H-imidazole-2-carbaldehyde

To a suspension of imidazole-2-carboxaldehyde (1.00 g, 10.4 mmol) in DMF(16 mL) was added N,N-diisopropylethylamine (4.0 mL, 23.0 mmol) followedby a solution of trityl chloride (3.19 g, 11.4 mmol) in DMF (10 mL), andthe mixture was stirred at 30° C. for 21 h. The mixture was concentratedin vacuo then dissolved in EtOAc (60 mL). The solution was washed withsaturated NaHCO₃(aq) (2×30 mL) and brine (15 mL) then dried (MgSO₄) andconcentrated in vacuo. Purification of the crude material by columnchromatography on silica gel (20% EtOAc/hexanes) gave a yellow solid(1.63 g, 46%). ¹H NMR (CDCl₃) δ 7.03 (s, 1H), 7.12 (m, 6H), 7.32 (m,10H), 9.23 (s, 1H).

(E)-3-(1-Trityl-1H-imidazol-2-yl)-acrylic acid ethyl ester

Triethyl phosphonoacetate (1.24 mL, 6.25 mmol) was added dropwise to asuspension of sodium hydride (60% in mineral oil, 212 mg, 5.30 mmol) inDME (5 mL) and stirred at room temperature for 30 minutes. The solutionwas added to a suspension of 1-trityl-1H-imidazole-2-carbaldehyde (1.63g, 4.82 mmol) in DME (7 mL), and the mixture was heated at reflux for 15minutes then stirred at 60° C. for 1 hr. The reaction mixture wasquenched with H₂O (30 mL) and extracted with CH₂Cl₂ (3×15 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuo.Purification of the crude material by column chromatography on silicagel (25% EtOAc/hexanes) gave a yellow solid (1.32 g, 67%). ¹H NMR(CDC1₃) δ 1.13 (t, 3H, J=7.1 Hz), 4.00 (q, 2H, J=7.1 Hz), 6.52 (d, 1H,J=15 Hz), 6.70 (d, 1H, J=15 Hz), 6.87 (d, 1H, J=1.2 Hz), 7.13 (m, 7H),7.33 (m, 9H).

3-(1-Trityl-1H-imidazol-2-yl)-propan-1-ol

A solution of(E)-3-(1-trityl-1H-imidazol-2-yl)-acrylic acid ethyl ester(1.32 g, 3.23 mmol) in 4:1 MeOH/EtOAc (20 mL) was stirred at roomtemperature with a suspension of 10% Pd/C (132 mg, 0.124 mmol) underhydrogen atmosphere (1 atm) for 20 h. The catalyst was removed byfiltration, and the filtrate was concentrated in vacuo to give yellowcrystals (1.49 g).

To a solution of the crude ester from above (1.49 g) in THF (7 mL) wasadded LiA1H₄ (1.0 M/THF, 7.0 mL, 7.0 mmol) at 0° C., and the mixture wasstirred at room temperature for 1 h. Methanol (5 mL) was added followedby 1 N NaOH(aq) (40 mL), and the mixture was extracted with CH₂Cl₂ (2×25mL). The combined organic extracts were dried (MgSO₄) and concentratedin vacuo. ¹H NMR (CDCl₃) δ 1.37 (m, 2H), 2.09 (m, 2H), 3.51 (m, 2H),6.68 (d, 1H, J=1.5 Hz), 6.92 (d, 1H, J=1.5 Hz), 7.13 (m, 6H), 7.33 (m,9H).

3-(1-Trityl-1H-imidazol-2-yl)-propionaldehyde

To a solution of 3-(1-trityl-1H-imidazol-2-yl)-propan-1-ol (201 mg,0.545 mmol) in CH₂Cl₂ (6 mL) was added Dess-Martin periodinane (278 mg,0.655 mmol) at room temperature. After stirring at room temperature for1 h, the mixture was diluted with EtOAc (30 mL), washed with 1 NNaOH(aq) (2×10 mL) and brine (10 mL), then dried (MgSO₄) andconcentrated in vacuo to give a tan foam (178 mg, 89%). ¹H NMR (CDCl₃) δ2.19 (m, 2H),2.37 (m, 2H), 6.75 (d, 1H, J=1.5 Hz), 6.93 (d, 1H, J=1.5Hz), 7.13 (m, 6H), 7.34 (m, 9H), 9.54 (s, 1H).

(1H-Benzimidazol-2-ylmethyl)-[3-(1H-imidazol-2-yl)-propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(COMPOUND 13)

Using General Procedure B: To a stirred solution of2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylicacid tert-butyl ester (184 mg, 0.486 mmol) and3-(1-trityl-1H-imidazol-2-yl)-propionaldehyde (178 mg, 0.486 mmol) inTHF (5 mL) was added NaBH(OAc)₃ (206 mg, 0.972 mmol), and the mixturewas stirred at room temperature for 3.5 h. Purification of the crudematerial by column chromatography on silica gel (200:5:1CH₂Cl₂/MeOH/NH₄OH) afforded a yellow oil (168 mg) that was determined by¹H NMR to be a mixture of2-({(5,6,7,8-tetrahydro-quinolin-8-yl)-[3-(1-trityl-1H-imidazol-2-yl)-propyl]-amino}-methyl)-benzimidazole-1-carboxylicacid tert-butyl ester and 3-(1-trityl-1H-imidazol-2-yl)-propan-1-ol andwas used in the next step without further purification.

A solution of the crude amine from above (168 mg) in saturated HBr/AcOH(3 mL) was stirred at room temperature for 1 h then basified with 10 NNaOH(aq) and extracted with CH₂Cl₂ (3×10 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. Purification ofthe crude material by column chromatography on silica gel (300:5:1CH₂Cl₂/MeOH/NH₄OH) afforded(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-[3-(1-trityl-1H-imidazol-2-yl)-propyl]-amineas a yellow oil (101 mg, 33% over 2 steps).

To a solution of(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-[3-(1-trityl-1H-imidazol-2-yl)-propyl]-amine(101 mg, 0.161 mmol) in CH₂Cl₂ (1.6 mL) was added triethylsilane (0.38mL, 2.4 mmol) followed by TFA (1.9 mL, 25 mmol), and the solution wasstirred at room temperature for 21 h then concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ (15 mL) and washed with 1 N NaOH(aq) (10mL). The aqueous phase was extracted with CH₂Cl₂ (2×10 mL), and thecombined organic phases were dried (MgSO₄) and concentrated in vacuo.Purification of the crude material by column chromatography on silicagel (150:5:1 CH₂Cl₂/MeOH/NH₄OH) afforded COMPOUND 13 as a colourlessfoam (47 mg, 69%). ¹H NMR (CDCl₃) δ 1.62-1.93 (m, 4H), 2.02 (m, 1H),2.16 (m, 1H), 2.58-2.88 (m, 6H), 3.91 (d, 1H, J=16 Hz), 3.98 (d, 1H,J=16 Hz), 4.02 (m, 1H), 6.86 (s, 2H), 7.18 (m, 3H), 7.43 (d, 1H, J=7.2Hz), 7.55 (m, 2H), 8.55 (d, 1H, J=3.6 Hz); ¹³C NMR (CDCl₃) δ 21.52,23.71, 25.96, 26.67, 29.43, 49.21, 51.07, 62.23, 115.28, 120.75, 122.41,122.81, 135.47, 138.23, 138.86, 146.68, 148.71, 155.28, 157.49. ES-MSm/z 387 (M+H). Anal. Calcd. for C₂₃H₂₆N₆.0.21H₂O.0.36CH₂Cl₂: C, 66.67;H, 6.50; N, 19.97. Found: C, 66.77; H, 6.65; N, 19.69.

Example 14

COMPOUND 14: Preparation ofN-(6-2-[(1H-Benzimidazol-2-ymethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-ethylamino{-pyridin-3-yl)-acetamide

To a solution of2-{[[2-(5-Nitro-pyridin-2-ylamino)-ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (see COMPOUND 11) (316 mg, 0.58 mmol) in AcOH (4mL) was added iron powder (172 mg, 3.08 mmol) and the reaction heated toreflux for 2 h. The mixture was cooled to room temperature, diluted withwith water (5 mL) and extracted with CH₂Cl₂ (3×25 mL). The combinedorganic extracts were dried (Na₂SO₄), concentrated in vacuo and purifiedby radial chromatography on silica gel (1 mm plate, 100:1:1CH₂Cl₂/MeOH/NH₄OH then 50:1:1) to give the desired product (96 mg, 30%)as a clear oil.

Using General Procedure D: Conversion of the free base (25 mg, 0.055mmol) to the hydrobromide salt, followed by re-precipitation of theintermediate solid from methanol/ether, gave COMPOUND 14 (36 mg) as awhite solid. ¹H NMR (D₂O) δ 1.83-1.90 (m, 1H), 2.05-2.20 (m, 2H), 2.14(s, 3H), 2.39-2.43 (m, 1H), 2.86-2.94 (m, 1H), 3.01-3.0 (m, 2H),3.18-3.25 (m, 1H), 3.39-3.49 (m, 2H), 4.38 (d, 1H, J=16.5 Hz), 4.58 (d,1H, J=16.5 Hz), 4.62-4.68 (m, 1H), 6.75 (d, 1H, J=9.6 Hz), 7.47 (dd, 2H,J=6, 3 Hz), 7.49 (s, 1H), 7.60 (dd, 2H, J=6, 3 Hz), 7.83 (s, 1H), 7.89(t, 1H, J=6.6 Hz), 8.38 (d, 1H, J=7.8 Hz), 8.71 (d, 1H, J=6.6 Hz); ¹³CNMR (D₂O) δ 20.39, 20.84, 23.07, 27.83, 41.24, 49.13, 50.29, 62.01,113.37, 114.24, 125.70, 125.82, 126.11, 126.96, 130.58, 138.24, 139.94,141.08, 148.39, 149.47, 150.18, 151.32, 172.99; ES-MS m/z 456 (M+H).Anal. Calcd. for C₂₆H₂₉N₇O. 3.2 HBr.2.4 H₂O: C, 41.21; H, 4.92; N,12.94; Br, 33.75. Found: C, 41.12; H, 4.98; N, 12.77; Br, 34.06.

Example 15

COMPOUND 15: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine(hydrobromide salt) Preparation ofN-(tert-butoxycarbonyl)-3-amino-propionaldehyde

To a solution of tert-butyl N-(3-hydroxypropyl)carbamate (0.177 g, 1.01mmol) in CH₂Cl₂ (5 mL) was added Dess-Martin periodinane (0.545 g, 1.28mmol) and the resultant mixture was stirred at room temperature for 2.5hours. The mixture was diluted with ether (20 mL) and treated with 20%aqueous Na₂S₂O₃ (5 mL) and saturated aqueous NaHCO₃ (5 mL). After 10minutes the mixture became clear and colorless and the phases wereseparated. The aqueous phase was extracted with ether (3×10 mL). Thecombined organic extracts were washed sequentially with 20% aqueousNa₂S₂O₃ (10 mL), saturated aqueous NaHCO₃ (10 mL), and brine (10 mL),dried (MgSO₄), and concentrated to provide 0.127 g (96%) ofN-(tert-butoxycarbonyl)-3-amino-propionaldehyde as a colorless oil. ¹HNMR (CDCl₃) δ 1.43 (s, 9H), 2.71 (t, 2H, J=6.0 Hz), 3.42 (m, 2H), 4.89(br s, 1H), 9.81 (s, 1H).

Using General Procedure B: Reaction ofN-(tert-butoxycarbonyl)-2-amino-propionaldehyde (0.127 g, 0.73 mmol) and(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.152 g, 0.55 mmol) with NaBH(OAc)₃ (0.262 g, 1.24 mmol) in CH₂Cl₂ (5mL) for 18 hours followed by purification of the crude material byradial chromatography on silica gel (2 mm plate, 50:1:1CH₂Cl₂—CH₃OH—NH₄OH) provided 0.169 g of a yellow foam. The foam wasdissolved in CH₂Cl₂ (2 mL) and treated with trifluoroacetic acid (1 mL).The resultant solution was stirred at room temperature for 2 hours thenconcentrated under reduced pressure. The residue was dissolved in CH₂Cl₂(10 mL) and treated with NaOH (10 M, ˜2 mL) until the aqueous phase wasbasic (pH 14). The phases were separated and the aqueous phase wasextracted with CH₂Cl₂ (3×5 mL). The combined organic extracts were dried(Na₂SO₄) and concentrated. Purification of the crude material by radialchromatography on silica gel (1 mm plate, 10:1:1 CH₂Cl₂—CH₃OH—NH₄OH)provided 57 mg of a white foam.

Using General Procedure D: Conversion of the free base (57 mg) to thehydrobromide salt, followed by re-precipitation of the intermediatesolid from methanol/ether, gave COMPOUND 15 (75 mg) as a white solid. ¹HNMR (D₂O) δ 1.77-2.09 (m, 4H), 2.18-2.22 (m, 1H), 2.38-2.42 (m, 1H),2.60-2.70 (m, 1H), 2.87-2.97 (m, 3H), 3.01-3.04 (m, 2H), 4.42 (d, 1H,J=16.8 Hz), 4.51-4.49 (m, 2H), 7.60-7.63 (m, 2H), 7.79-7.90 (m, 3H),8.36 (d, 1H, J=7.8 Hz), 8.65 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ 20.41(2carbons), 26.38, 27.66, 37.69, 47.94, 49.13, 60.39, 114.32, 126.02,126.98, 131.10, 139.50, 140.73, 148.18, 150.96, 151.36; ES-MS m/z 336(M+H). Anal. Calcd. for C₂₀H₂₅N₅.3.0HBr.1.6H₂O: C, 39.57; H, 5.18; N,11.54; Br, 39.49. Found: C, 39.85; H, 5.10; N, 11.45; Br, 39.15.

Example 16

COMPOUND 16: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N²-pyridin-2-ylmethyl-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine(hydrobromide salt)

To a solution of N¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine hydrobromidesalt [COMPOUND 10] (98 mg, 0.168 mmol) in H₂O (2 mL) was added NaOH (10M, 2 mL). The resultant solution was extracted with CH₂Cl₂ (4×5 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated andprovided 53 mg of the free base. To a solution of the free base fromabove (53 mg, 0.165 mmol) in methanol (2 mL) was addedpyridine-2-carboxaldehyde (20 μL, 0.210 mmol) and the resultant solutionwas stirred at room temperature for 2 hours. NaBH₄ (36 mg, 0.95 mmol)was added and the mixture was stirred for 15 minutes. The mixture wasconcentrated and the residue was partitioned between CH₂Cl₂ (10 mL) andbrine (5 mL). The phases were separated and the aqueous phase wasextracted with CH₂Cl₂ (3×5 mL). The combined organic extracts were dried(Na₂SO₄) and concentrated. Purification of the crude material by radialchromatography on silica gel (1 mm plate, 25:1:1 CH₂Cl₂—CH₃OH—NH₄OH)provided 34 mg (45%) of the free base of the title compound.

Using General Procedure D: Conversion of the free base (34 mg) to thehydrobromide salt, followed by re-precipitation of the intermediatesolid from methanol/ether, gave COMPOUND 16 (57 mg) as a white solid. ¹HNMR (D₂O) δ 1.78-1.90 (m, 1H), 1.98-2.11 (m, 1H), 2.17-2.22 (m, 1H),2.39-2.43 (m, 1H), 2.97-3.09 (m, 3H), 3.25-3.37 (m, 3H), 4.39 (d, 1H,J=16.5 Hz), 4.47 (d, 2H, J=2.4 Hz), 4.54-4.59 (m, 2H), 7.57-7.65 (m,4H), 7.77-7.88 (m, 3H), 8.04 (dt, 1H, J=1.5, 7.5 Hz), 8.35 (d, 1H, J=7.8Hz), 8.50 (d, 1H, J=4.8 Hz), 8.61 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ20.27, 20.54, 27.67, 45.45, 47.48, 48.12, 50.32, 60.32, 114.42, 125.85,126.11, 126.19, 127.27, 130.98, 139.83, 141.03, 141.70, 147.87, 148.39(2 carbons), 149.85, 150.06; ES-MS m/z 413 (M+H). Anal. Calcd. forC₂₅H₂₈N₆.4.1HBr.2.0 H₂O: C, 38.48; H, 4.66; N, 10.77; Br, 41.98. Found:C, 38.69; H, 4.78; N, 10.60; Br, 41.70.

Example 17

COMPOUND 17: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.169 g, 0.451 mmol) in CH₃CN (5 mL) was addedN,N-diisopropylethylamine (0.25 mL, 1.44 mmol) followed by4-bromobutyronitrile (0.10 ml, 1.01 mmol). The resultant mixture washeated to 80° C. for 5 d then cooled to room temperature. The mixturewas concentrated and the residue was partitioned between CH₂Cl₂ (20 mL)and brine (10 mL). The phases were separated and the aqueous phase wasextracted with CH₂Cl₂ (3×10 mL). The combined organic extracts weredried (Na₂SO₄) and concentrated. Purification of the crude material bycolumn chromatography on silica gel (30:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided108 mg (54%) of a yellow foam.

The intermediate from above (108 mg, 0.24 mmol) was dissolved in NH₃saturated methanol (4 mL), treated with Raney nickel (100 mg), andplaced under 50 psi H₂ on a Parr shaker, for 24 h. The mixture wasfiltered through Celite© and the cake was washed with methanol. Theeluant was concentrated under reduced pressure. Purification of thecrude material by radial chromatography on silica gel (1 mm plate,20:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided 33 mg (39%) of the free base of thetitle compound as a white foam.

Using General Procedure D: Conversion of the white foam (33 mg) to thehydrobromide salt, followed by re-precipitation of the intermediatesolid from methanol/ether, gave COMPOUND 17 (40 mg) as a white solid. ¹HNMR (D₂O) δ 1.52 (br s, 4H), 1.74-1.88 (m, 1H), 1.95-2.08 (m, 1H),2.15-2.21 (m, 1H), 2.34-2.39 (m, 1H), 2.50-2.61 (m, 1H), 2.79-2.86 (m,3H), 2.99-3.02 (m, 2H), 4.38 (d, 1H, J=16.8 Hz), 4.47-4.56 (m, 2H),7.58-7.63 (m, 2H), 7.76-7.88 (m, 3H), 8.34 (d, 1H, J=7.8 Hz), 8.62 (d,1H, J=5.7 Hz); ¹³C NMR (D₂O) δ 20.42(2 carbons), 25.03, 25.42, 27.64,39.50, 48.20, 51.71, 60.64, 114.26, 125.93, 126.93, 131.05, 139.32,140.62, 148.09, 150.31, 151.82; ES-MS m/z 350 (M+H). Anal. Calcd. forC₂₁H₂₇N₅.2.9 HBr.2.2 H₂O: C, 40.44; H, 5.54; N, 11.23; Br, 37.15. Found:C, 40.38; H, 5.42; N, 10.85; Br, 37.42.

Example 18

COMPOUND 18: Preparation ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine(hydrochloride salt) Preparation of 4-phthalamido-butyraldehyde

A solution of 4-amino-1-butanol (5.0 g, 56 mmol) and phthalic anhydride(8.3 g, 56 mmol) in 20% MeOH/CHCl₃ (140 mL) was stirred at reflux for 66h. The mixture was cooled to room temperature and washed sequentiallywith water (3×75 mL) and 1N NaOH (3×50 mL). The separated organic layerwas dried (MgSO₄), concentrated, and purified by flash chromatography (5cm id., 120 g silica gel, eluted with 2% MeOH/CH₂Cl₂) to give thedesired alcohol as a white solid (4.21 g, 34%).

To a stirred slurry of TPAP (340 mg, 0.96 mmol), NMO (3.4 g, 29 mmol)and 3 Å molecular seives (10 g) in CH₂Cl₂ (100 mL) was added dropwise asolution of the alcohol from above (4.2 g, 19 mmol) in CH₂Cl₂ (50 mL)over 30 min. The black slurry was stirred under N₂ for 30 min after theaddition, concentrated in vacuo, and purified by flash chromatography (5cm id., 80 g silica gel, eluted with EtOAc) to afford the pure titlecompound as a grey solid (3.30 g, 80%). ¹H NMR (CDCl₃) δ 1.97-2.07 (m,2H), 2.54 (t, 2H, J=7.2 Hz), 3.74 (t, 2H, J=6.8 Hz), 7.71-7.75 (m, 2H),7.82-7.88 (m, 2H), 9.77 (s, 1H).

Using General Procedure B: 4-phthalamido-butyraldehyde from above (3.21g, 14.8 mmol) was reacted withS-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (2.40 g, 16.3 mmol) andNaBH(OAc)₃ (9.54 g, 45.0 mmol) in dichloromethane (150 mL). Flashchromatography (5 cm id, 200 g silica gel, eluted with 5% MeOH/CH₂Cl₂)provided the pure 2° amine as a white foamy solid (2.48 g, 48%).

To a solution of the amine from above (2.5 g, 7.1 mmol) in acetonitrile(70 mL) was added diisopropylethylamine (1.9 mL, 10.7 mmol),1-boc-2-chloromethylbenzimidazole (2.3 g, 8.6 mmol), and potassiumiodide (115 mg, 0.70 mmol). The mixture was stirred under an N₂atmosphere at 60° C. for 15 h, cooled to room temperature andconcentrated in vacuo. The residue was partitioned between chloroform(150 mL) and water (100 mL). The separated organic layer was dried(MgSO₄), concentrated, and purified by flash chromatography (5 cm id,120 g silica gel, eluted with CH₂Cl₂ to remove unreacted chloride then2% MeOH/CH₂Cl₂ to remove desired product) to give the desired amine as apale yellow foamy solid (3.50 g, 85%).

A solution of the amine from above (3.33 g, 5.7 mmol) in ethanol (30 mL)was treated with hydrazine monohydrate (1.80 g, 36 mmol), stirred forthree hours. The mixture was then concentrated in vacuo and purified byflash chromnatography (5 cm id., 80 g silica gel, eluted with 5%MeOH/CH₂Cl₂) to give the unprotected amine as a pale yellow foamy solid(1.70 g, 86%).

The amine from above (1.70 g, 4.86 mmol) was dissolved in glacial aceticacid (5 mL) and treated with HCl saturated acetic acid (5 mL). Thesolution was allowed to stir at room temperature 5 min, then it wasslowly dropped into diethyl ether (400 mL) with vigorous stirring. Theresultant slurry was suction filtered through a glass fritted funnel andthe filter cake was washed with diethyl ether (3×100 mL) and dried in avacuum oven at 40° C. for 16 h to give COMPOUND 18 as a white solid(2.34 g, 94%). ¹H NMR (D₂O) δ 1.46-1.63 (m, 4H), 1.70-1.87 (m, 1H),1.97-2.07 (m, 1H), 2.10-2.21 (m, 1H), 2.28-2.38 (m, 1H), 2.55-2.65 (m,1H), 2.81-2.90 (m, 3H), 2.91-3.00 (m, 2H), 4.30 (d, 1H, J=16.3 Hz), 4.41(d, 1H, J=16.3 Hz), 4.42-4.48 (m, 1H), 7.48-7.51 (m, 2H), 7.70-7.75 (m,3H), 8.20 (d, 1H, J=8.2 Hz), 8.53 (d, 1H, J=4.5 Hz); ¹³C NMR (D₂O) δ20.36, 20.43, 21.67, 24.99, 25.24, 27.60, 39.51, 48.29, 51.78, 60.54,114.46 (2 carbons), 125.63, 126.10 (2 carbons), 132.53, 139.58, 140.16,147.34, 151.41, 151.81. ES-MS m/z 350 (M+H). Anal. Calcd. forC₂₁H₂₇N₅.2.5HCl.2.0H₂O.0.6CH₃COOH: C, 52.01; H, 7.06; N, 13.66; Cl,17.29. Found: C, 52.15; H, 7.09; N, 13.40; Cl, 17.56.

The enantiomeric purity of COMPOUND 18 was determined to be 96.7% bychiral HPLC using the following conditions: Instrument: Hewlett Packard1100 HPLC (VWD1); Column: Chiralpak OD, 0.46 cm×25 cm; Mobile Phases: A:90:10 hexanes/isopropanol with 0.1% DEA, B: isopropanol; Isocratic: 90%A, 10% B; Total Run Time: 20 min; Flow Rate: 0.5 mL/min; Temperature:10° C.; Detector: UV @ 270 nm; Injection volume: 20 μL.

Retention time of the S enantiomer=16.3 min.

Retention time of the R enantiomer=21.9 min.

Example 19

COMPOUND 19: Preparation ofN¹-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dionewas prepared following the procedure for COMPOUND 18.2-{4-[(1-Methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dionewas prepared following the general procedure for reductive aminations.

To a solution of2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(0.2011 g, 0.58 mmol) in dichloromethane (5.8 mL) was added1-Methyl-1H-benoimidazole-2-carbaldehyde (0.1844 g, 1.15 mmol) andNaBH(OAc)₃ (0.2462 g, 1.16 mmol), and was stirred at room temperaturefor four days. The organic phase was washed with NaHCO₃ (2×10 mL), driedover Na₂SO₄, filtered, and concentrated. Purification of the crudematerial by column chromatography on silica gel (47:2:1CH₂Cl₂—MeOH—NH₄OH) provided 103 mg (36%) of2-{4-[(1-Methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione.¹H NMR (CDCl₃) δ 1.30-1.44 (m, 2H), 1.48-1.63 (m, 3H), 1.84-1.96 (m,2H), 2.03-2.07 (m, 1H), 2.54-2.81 (m, 4H), 3.51 (t, 2H, J=7.2 Hz), 3.95(s, 3H), 3.99-4.06 (m, 2H), 4.19 (d, 1H, J=13.5Hz), 6.94-6.98 (m, 1H),7.13-7.21 (m, 2H), 7.24-7.29 (m, 2H), 7.63-7.68 (m, 3H), 7.74-7.78 (m,2H), 8.40 (d, 1H, J=3.6 Hz).

To a solution of2-{4-[(1-Methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione(0.1030 g, 0.21 mmol) in ethanol (1 mL) was added hydrazine monohydrate(0.51 mL, 10.5 mmol), and the reaction mixture was stirred at roomtemperature for 18 hours. The mixture was concentrated and purifiedfirst via column chromatography on silica gel (91:12:1CH₂Cl₂—MeOH—NH₄OH) and then by radial chromatography on silica (18:1:1CH₂Cl₂—MeOH—NH₄OH) to yield 0.0246 g (32%) ofN¹-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine.¹H NMR (CDCl₃) δ 1.32-1.42 (m, 5H), 1.91-2.02 (m, 2H), 2.05-2.11 (m,1H), 2.55 (t, 2H, J=6.9 Hz), 2.60-2.64 (m, 3H), 2.76-2.86 (m, 1H), 3.98(s, 3H), 4.04-4.17 (m, 3H), 7.00-7.04 (m, 1H), 7.21-7.27 (m, 2H),7.30-7.33 (m, 2H), 7.68-7.72 (m, 1H), 8.47 (d, 1H, J=3.3 Hz).

Following a general procedure D,N¹-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diaminewas salted out. To a solution ofN¹-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(0.0246 g, 0.068 mmol) in acetic acid (0.8 mL) was added HBr/AcOH (1mL), followed by the addition of diethyl ether (50 mL), which resultedin the precipitation of the salt. The ether was decanted off and theremaining solid was washed with diethyl ether (2×50 mL). Any residualdiethyl ether was removed by vacuum and methanol (1 mL) was added to thesolid. Again, diethyl ether (50 mL) was added and the salt was washedwith diethyl ether (3×50 mL) to give COMPOUND 19 (23 mg, 76%) as a whitesolid. ¹H NMR (D₂O) δ 1.52-1.53 (m, 4H), 1.73-1.87 (m, 1H), 1.99-2.11(m, 1H), 2.15-2.19 (m, 1H), 2.40-2.43 (m, 1H), 2.51-2.58 (m, 1H),2.78-2.84 (m, 3H), 2.97-2.99 (m, 2H), 3.96 (s, 3H), 4.38 (d, 1H, J=17.7Hz), 4.48-4.54 (m, 1H), 4.59 (d, 1H, J=17.7 Hz), 7.58-7.61 (m, 2H),7.75-7.84 (m, 3H), 8.30 (d, 1H, J=7.8 Hz), 8.58 (d, 1H,J=5.4Hz); ¹³CNMR(D₂O) 20.44 (2H), 25.03, 25.44, 27.69, 31.52, 39.47, 47.70, 52.18,60.88, 112.80, 114.22, 125.88, 126.73, 127.12, 130.08, 133.45, 139.32,140.64, 148.09, 151.13, 151.68. ES-MS m/z 364 (M+H). Anal. Calcd. forC₂₂H₂₉N₅.3.2HBr2.2H₂O: C, 39.91; H, 5.57; N, 10.58; Br, 38.62. Found: C,39.97; H, 5.44; N, 10.37; Br, 38.49.

Example 20

COMPOUND 20: Preparation ofN¹-[5-(4-Fluoro-phenyl)-1H-imidazol-2-ylmethyl]-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3 -dionewas prepared following the general procedure B for reductive amination.To a solution of 5,6,7,8-Tetrahydro-quinolin-8-ylamine (1.0609 g, 7.1mmol) and 4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (1.4079g, 6.8 mmol) (prepared according to the procedure for COMPOUND 18) inmethylene chloride (64 mL) was added NaBH(OAc)₃ (4.07 g, 19.2 mmol) andthe reaction stirred at room temperature for two hours. The reaction wasquenched with 1N NaOH (45 mL), extracted with methylene chloride (2×55mL), dried (Na₂SO₄), filtered, and concentrated. Purification of thecrude material by column chromatography on silica gel (40:1:1CH₂Cl₂—MeOH—NH₄OH) provided 1.16 g (52%) of2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione.¹H NMR (CDCl₃) δ 1.57-1.66 (m, 3H), 1.69-1.84 (m, 4H). 1.93-2.03 (m,1H), 2.07-2.13 (m, 1H), 2.69-2.86 (m, 4H), 3.70-3.77 (m, 3H), 7.03-7.07(m, 1H), 7.35 (d, 1H, J=7.2 Hz), 7.67-7.73 (m, 2H), 7.80-7.85 (m, 2H),8.37 (d, 1H, J=3 Hz).

To a solution of4-(4-Fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde(0.2301 g, 0.72 mmol) in methylene chloride (7.2 mL) was added2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(0.3030 g, 0.87 mmol) and then NaBH(OAc)₃ (0.3060 g, 1.44 mmol), and thereaction mixture was stirred at room temperature for four days. Thereaction was quenched with saturated NaHCO₃ (6 mL), extracted withCH₂Cl₂ (2×25 mL), dried (Na₂SO₄), filtered, and concentrated.Purification of the crude material by column chromatography on silicagel (50:1:1 CH₂Cl₂—MeOH—NH₄OH) provided 0.3125 g (66%) of2-{4-[[5-(4-Fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione.¹H NMR (CDCl₃) δ 0.82-0.87 (m, 2H), 1.25-1.37 (m, 2H), 1.48-1.69 (m,10H), 1.88-2.08 (m, 3H), 2.56-2.82 (m, 4H), 3.38-3.44 (m, 2H), 3.53 (t,2H, J=7.2 Hz), 3.96 (s, 2H), 4.01-4.04 (m, 1H), 5.56 (d, 1H, 10.8 Hz),5.79 (d, 1H, J=10.5 Hz), 6.97-7.03 (m, 3H), 7.12 (s, 1H), 7.30 (d, 1H,J=7.5 Hz), 7.61-7.70 (m, 4H), 7.75-7.79 (m, 2H), 8.44 (d, 1H, J=4.5 Hz).

To a solution of2-{4-[[5-(4-Fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8yl)-amino]-butyl}-isoindole-1,3-dione(0.3125 g, 0.48 mmol) in ethanol (5 mL) was added hydrazine monohydrate(0.12 mL), and the reaction mixture was stirred at room temperature for17 hours. The reaction mixture was concentrated, and purified via columnchromatography on silica gel (20:1:1 CH₂Cl₂—MeOH—NH₄OH) to yield 0.1838g (73%) ofN¹-[5-(4-Fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine.¹H NMR (CDCl₃) δ 0.85 (t, 2H, J=8.1 Hz), 1.25-1.34 (m, 7H), 1.61-1.72(m, 1H), 1.89-2.05 (m, 4H), 2.54-2.82 (m, 8H), 3.35-3.47 (m, 3H), 3.93(s, 2H), 4.06 (t, 1H, J=8.1 Hz), 5.53 (d, 2H, J=10.5 Hz), 5.78 (d, 2H,J=10.8 Hz), 6.99-7.04 (m, 3H), 7.15 (s, 1H), 7.31 (d, 1H, J=7.5 Hz),7.66-7.70 (m, 2H), 8.47 (d, 1H, J=3.6 Hz).

To a solution ofN¹-[5-(4-fluro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-N1-(5,6,7,8-tetrahydro-quinolin-8-1)-butane-1,4-diamine(0.1838 g, 0.35 mmol) in methylene chloride (5 mL) was added TFA (5 mL),and was stirred in a room temperature for 3 days. The mixture wasconcentrated, dissolved in CH₂Cl₂, and neutralized with 10N NaOH. Theaqueous phase was extracted with CH₂Cl₂ (4 times), and the combinedorganic extracts were then washed with brine, dried (Na₂SO₄), filteredand concentrated. The crude material was purified by columnchromatography on silica gel (15:1:1 CH₂Cl₂MeOH—NH₄OH) and then byradial chromatography on silica (15:1:1 CH₂Cl₂MeOH—NH₄OH) to giveCOMPOUND 20 (0.0421 G, 31%) as an orange oil. ¹H NMR (CDCl₃) δ 1.25-1.43(m,4H), 1.62-1.75 (m, 1H), 1.84-1.92 (m, 1H), 1.96-2.05 (m, 1H),2.13-2.15 (m, 1H), 2.44-2.50 (m, 3H), 2.63-2.73 (m, 2H), 2.79-2.89 (m,1H), 3.87 (s, 1H), 3.99-4.04 (m, 2H), 7.04 (t, 2H, J=9 Hz), 7.10-7.14(m, 1H), 7.23 (s, 1H), 740 (d, 1H, J=7.5 Hz), 7.65-7.70 (m, 2H), 8.50(d, 1H, J=4.2 Hz); ¹³ C NMR (CDCl₃) δ 21.70, 23.02, 26.37, 29.57, 30.17,41.44, 49.02, 50.72, 61.70, 115.83 (d, 2C, J=14.34 Hz), 122.49, 126.43(d, 2C, J=5.18 Hz), 130.26, 135.01, 137.74, 147.14 (2C), 149.64, 157.77,160.34, 163.58. ES-MS m/z 394 (M+H). Anal. Calcd. ForC23H28N5F.1.3CH₂Cl₂: C, 70.20; H, 7.17; N, 17.80. Found: C, 58.09; H,6.23; N, 13.59.

Example 21

COMPOUND 21: Preparation ofN′-(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-N-benzyl-1,4-butanediamine(hydrobromide salt)

To a solution ofN′-(1-(2-trimethylsilyl)-ethan-1yloxymethyl)-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-1,4-butanediamine(70 mg, 0.15 mmol) in methanol (4 mL) was added benzaldehyde (0.015 mL,0.15 mmol). The mixture was stirred overnight at room temperature, thencooled to 0° C. Sodium borohydride (38 mg, 1.0 mmol) was then added, andthe reaction was stirred for one hour, gradually warming to roomtemperature. The solution was then concentrated. The residue was takenup in dichloromethane and washed with 1N sodium hydroxide (3 mL), thendried over anhydrous sodium sulfate, concentrated and purified bychromatography on silica gel (10:1 dichloromethane:methanol) to affordN′-(1-(2-trimethylsilyl)-ethan-1yloxymethyl)-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-N-benzyl-1,4-butanediamine(39 mg, 49%). ¹H NMR (CDCl₃) δ 0.10(s, 9H), 0.80 (t, 2H, J=7.0 Hz), 1.41(m, 3H), 1.76-2.21 (m, 5H), 2.44 (m, 2H), 2.46-2.26 (m, 2H), 3.35 (t,2H, J=7.0 Hz), 3.67 (s, 2H), 4.06 (m, 1H), 4.08 (d, 1H, J=15.8 Hz), 4.22(d, 1H, J=15.8 Hz), 5.80 (d, 1H, J=14.6 Hz), 6.02 (d, 1H, J=14.6 Hz),7.00 (m, 1H), 7.27 (m, 8H), 7.42 (m, 1H), 7.80 (m, 1H), 8.44 (d, 1H,J=4.8 Hz).

as taken up in acetic acid (1 mL), to which a saturated solution of HBrin acetic acid (1 mL) was added. The mixture was then stirred,precipitated and isolated as per procedure D to yield COMPOUND 21 as awhite crystalline solid (26 mg). ¹H NMR (D₂O). δ 1.52 (m, 4H), 1.88 (m,1H), 2.01 (m, 1H), 2.08 (m, 1H), 2.31 (m, 1H), 2.44 (m, 1H), 2.88 (m,1H), 3.00 (t, 2H, J=6.9 Hz), 3.03 (m, 2H), 4.13 (s, 1H), 4.31 (d, 1H,J=16.1 Hz), 4.47 (m, 1H), 4.49 (d, 1H, J=16.1 Hz), 7.36 (m, 5H), 7.60(m, 2H), 7.77 (m, 2H), 7.83 (m, 1H), 8.26 (d, 1H, J=7.8 Hz), 8.68 (d,1H, J=4.9 Hz). ¹³C NMR (D₂O) δ 20.41, 23.68, 25.45, 27.63, 46.86, 48.24,51.34, 51.57, 60.63, 114.25, 125.93, 126.95, 129.66, 130.08, 130.17,130.98, 139.30, 140.60, 148.10, 151,24, 151.77. ES-MS m/z 440 (M+H);Anal. Calcd. for (C₂₈H₃₃N₅×3.1 HBr×1.4 H₂O); C, 46.99; H, 5.48; N, 9.79;Br 34.61. Found: C, 47.00; H, 5.44; N, 9.54; Br, 34.57.

Example 22

COMPOUND 22: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N⁴-pyridin-2-ylmethyl-N¹-(5,6,7,8-tetrahydro-guinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

Using General Procedure B (Two step reductive amination): Reaction ofN¹-(1-(2-(triethylsilyl)ethoxymethyl)-1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(101 mg, 0.21 mmol) with pyridine-2-carboxaldehyde (30 mL, 0.32 mmol) inCH₃OH (4 mL) for 6 hours and with NaBH₄ (35 mg, 0.92 mmol) for 40minutes followed by purification of the crude material by radialchromatography on silica gel (1 mm plate, 20:1:1 CH₂Cl₂—CH₃OH—NH₄OH)provided 84 mg (70%) of a colorless oil. The oil from above (84 mg, 0.15mmol) was dissolved in 6 N HCl (2 mL), heated at 50° C. for 4.5 hoursthen cooled to room temperature. The solution was treated with 10 N NaOH(2 mL) and extracted with CH₂Cl₂ (3×10 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated. Purification of the crudematerial by radial chromatography on silica gel (1 mm plate, 10:1:1CH₂Cl₂—CH₃OH—NH₄OH) provided 41 mg (63%) of the free base of the titlecompound as a colorless oil.

Using General Procedure D: Conversion of the oil from above (41 mg,0.092 mmol) to the hydrobroride salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 22 (72 mg, 93%) asa white solid. ¹H NMR (D₂O) δ 1.50-1.66 (m, 4H), 1.79-1.89 (m, 1H),1.96-2.08 (m, 1H), 2.15-2.20 (m, 1H), 2.35-2.39 (m, 1H), 2.50-2.60 (m,1H), 2.80-2.88 (m, 1H), 3.00-3.10 (m, 4H), 4.36-4.56 (m, 5H), 7.58-7.63(m,2H), 7.72-7.88 (m, 5H), 8.22 (dt, 1H, J=1.5, 7.8 Hz), 8.35 (d, 1H,J=8.1 Hz), 8.62 (d, 1H, J=5.7 Hz), 8.66 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O)δ 20.43(2 carbons), 23.77, 25.43, 27.65, 47.86, 48.23, 49.66, 51.64,60.64, 114.26, 125.94, 126.42, 126.54, 126.95, 130.97, 139.33, 140.62,143.16, 146.99, 148.09, 148.11, 151.23, 151.76. ES-MS m/z 441 (M+H).Anal. Calcd. for C₂₇H₃₂N₆.4.0HBr.3.7H₂O: C, 39.03; H, 5.26; N, 10.11;Br, 38.47. Found: C, 39.04; N, 10.04; Br, 38.52.

Example 23

COMPOUND 23: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N⁴-(1H-indol-3-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(free base)

To a solution ofN¹-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(73 mg, 0.16 mmol) in CH₂Cl₂ (2 mL) was added trifluoroacetic acid (4mL) and the resultant solution was stirred at room temperature overnightthen concentrated under reduced pressure. The residue was dissolved inCH₂Cl₂ (10 mL) and water (5 mL) and treated with NaOH (10 M, ˜2 mL)until the aqueous phase was basic (pH 14). The phases were separated andthe aqueous phase was extracted with CH₂Cl₂ (3×10 mL). The combinedorganic extracts were dried (Na₂SO₄) and concentrated. Purification ofthe crude material by radial chromatography on silica gel (1 mm plate,15:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided 37 mg ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamineas a white foam.

Using General Procedure B (Two step reductive amination): Reaction ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(86 mg, 0.25 mmol) with indole-3-carboxaldehyde (55 mg, 0.38 mmol) inCH₃OH (2.5 mL) overnight and with NaBH₄ (27 mg, 0.71 mmol) for 30minutes followed by purification of the crude material by radialchromatography on silica gel (1 mm plate, 50:1:1 CH₂Cl₂—CH₃OH—NH₄OH)provided 74 mg (60%) of COMPOUND 23 as a white solid. ¹H NMR (CDCl₃) δ1.38-1.52 (m, 4H), 1.64-1.73 (m, 1H), 1.83-1.95 (m, 1H), 2.00-2.05 (m,1H), 2.15-2.21 (m, 1H), 2.49-2.56 (m, 3H), 2.67-2.89 (m, 3H), 3.88 (s,2H), 3.96-4.10 (m, 3H), 7.03 (br s, 1H), 7.07-7.13 (m, 2H), 7.16-7.22(m, 3H), 7.35 (dd, 1H, J=7.8, 1.0 Hz), 7.40 (d, 1H, J=7.8 Hz), 7.58-7.60(m, 3H), 8.17 (br s, 1H), 8.55 (d, 1H, J=4.5 Hz); ¹³C NMR (CDCl₃) δ21.79, 23.58, 26.53, 27.64, 29.64, 44.94, 49.34, 49.88, 50.59, 61.83,111.66, 114.88, 118.99, 119.72, 121.96, 122.29, 122.51, 123.13, 127.42,135.05, 136.74, 137.72, 147.10, 156.87, 157.83. ES-MS m/z 479 (M+H).Anal. Calcd. for C₃₀H₃₄N₆.1.3 H₂O: C, 71.77; H, 7.35; N, 16.74. Found:C, 71.69; H, 7.14; N, 16.5.

Example 24

COMPOUND 24: Preparation of(1H-Benzimidazol-2-ylmethyl)-(3-piperidin-2-yl-propyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

A mixture of 3-(2-pyridyl)-1-propanol (0.75 mL, 5.83 mmol), PtO₂ (60 mg,0.26 mmol) and concentrated HCl (0.48 mnL, 5.86 mmol) in ethanol (3.1mL) was hydrogenated (50 psi) on a Parr shaker at room temperature for20 hours. The mixture was filtered through celite and the cake waswashed with methanol. The solvent was removed from the filtrate underreduced pressure and provided 1.34 g of a white slushy solid. The solid(1.34 g) was dissolved in THF (30 mL) and water (1 mL), treated withN,N-diisopropylethylamine (2.0 mL, 11.42 mmol) and di-tert-butyldicarbonate (2.16 g, 9.89 mmol) and the resultant mixture was stirred atroom temperature overnight. The reaction mixture was diluted with water(30 mL) and extracted with EtOAc (3×60 mL). The combined organicextracts were washed with brine (2×20 mL), dried (Na₂SO₄) andconcentrated. Purification of the crude material by columnchromatography on silica gel (2:1 hexanes-ethyl acetate) provided 1.38 g(97% from 3-(2-pyridyl)-1-propanol) ofN-tert-butoxycarbonyl-3-piperidin-2-yl-propan-1-ol as a colorless oil.¹H NMR (CDCl₃) δ 1.40-2.04 (m, 20H), 2.75 (t, 11H, J=12 Hz), 3.66-3.69(m, 1H), 3.94-3.96 (m, 1H), 4.25 (br s, 1H).

To a solution of N-tert-butoxycarbonyl-3-piperidin-2-yl-propan-1-ol(0.372 g, 1.53 mmol) in CH₂Cl₂ (7.5 mL), at room temperature, was addedsequentially 3 Å molecular sieves (0.814 g), N-methylmorpholine N-oxide(0.278 g, 2.37 mmol) and tetrapropylammonium perruthenate (56 mg, 0.16mmol). After 90 minutes, the mixture was filtered through a short columnof silica gel and the cake was washed with ethyl acetate. The solventwas removed from the filtrate under reduced pressure to provide 0.32 g(86%) of N-tert-butoxycarbonyl-3-piperidin-2-yl-propionaldehyde as agreen oil which was used without further purification.

Using general procedure B: Reaction ofN-tert-butoxycarbonyl-3-piperidin-2-yl-propionaldehyde (0.32 g, 1.33mmol) and(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.307 g, 1.10 mmol) with NaBH(OAc)₃ (0.448 g, 2.11 mmol) in CH₂Cl₂ (10mL) for 16 hours followed by purification of the crude material bycolumn chromatography on silica gel (30:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided0.285 g of a yellow foam. The foam (0.285 g) was dissolved in THF (10mL), treated with 3 N HCl (10 mL), and the resultant solution wasstirred at room temperature for 75 minutes. The pH of the solution wasadjusted to ˜14 using 10 N NaOH (˜4 mL). The solution was extracted withCH₂Cl₂ (4×30 mL) and the combined organic extracts were dried (Na₂SO₄)and concentrated. Purification of the crude material by columnchromatography on silica gel (25:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided 0.176g (40%) of the free base of the title compound as white foam.

Using General Procedure D: Conversion of the foam from above (69 mg,0.17 mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 24 (79 mg, 67%) asa white solid. NMR and HPLC analysis indicated a ˜1:1 mixture ofdiastereomers. ¹H NMR (D₂O) δ 1.18-1.53 (m, 7H), 1.78-1.84 (m, 4H),1.96-2.08 (m, 1H), 2.15-2.20 (m, 1H), 2.35-2.40 (m, 1H), 2.49-2.56 (m,1H), 2.81-3.00 (m, 5H), 3.28-3.32 (m, 1H), 4.35-4.56 (m, 3H), 7.59-7.62(m, 2H), 7.79-7.89 (m, 3H), 8.34 (br d, 1H, J=7.8 Hz), 8.63 (br d, 1H,J=5.4 Hz); ¹³C NMR (D₂O) δ 20.42(2 carbons), 21.82, 22.22, 24.03, 27.64,28.23, 31.02 & 31.11, 45.11,48.13 & 48.24, 51.76 & 51.88, 56.76 & 56.83,60.59 & 60.71, 114.25, 125.94, 126.97, 130.99, 139.31, 140.65, 148.11,151.26, 151.75. ES-MS m/z 404 (M+H). Anal. Calcd. forC₂₅H₃₃N₅.3.0HBr.3.2H₂O: C, 42.66; H, 6.07; N, 9.95; Br, 34.05. Found: C,42.47; H, 5.82; N, 9.78; Br, 34.43.

Example 25

COMPOUND 25: Preparation of4-[(1H-Benzoimidazole-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyraldehydeaminoguanidine hydrazone (hydrobromide salt)

Using General Procedure B: To a stirred solution of4-[(1H-Benzoimidazole-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyraldehyde(see COMPOUND 32 for preparation) (0.2182 g, 0.63 mmol) andaminoguanadine hydrochloride (69 mg, 0.63 mmol) in dry MeOH (4 mL) wasadded AcOH (75 μL, 1.26 mmol) and the mixture was stirred at roomtemperature for 3 h. The reaction was concentrated and the residue waspartitioned between CH₂Cl₂ (20 mL) and saturated aqueous NaHCO₃ (30 mL),the phases separated and the aqueous layer extracted with CH₂Cl₂ (2×15mL). The combined organic extracts were dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. Purification of the crude materialby radial chromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH,20:1:1 then 10:1:1) afforded the desired aminoguanidine hydrazone (69mg, 30%) as a pale yellow foam.

Using General Procedure D: Conversion of the foam from above (69 mg,0.17 mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 25 (93 mg, 76%) asa beige solid. ¹H NMR (D₂O) δ 1.54-1.77 (m, 2H), 1.78-1.94 (m, 1H),1.95-2.11 (m, 1H), 2.12-2.31 (m, 3H), 2.32-2.44 (m, 1H), 2.45-2.62 (m,1H), 2.79-2.91 (m, 1H), 2.96-3.08 (m, 2H), 4.35 (d, 1H, J=16.5 Hz), 4.50(d, 1H, J=16.5 Hz), 4.51-4.59 (m, 1H), 7.32 (t, 1H, J=5.1 Hz), 7.58-7.64(m, 2H), 7.77-7.81 (m, 2H), 7.88 (dd, 1H, J=7.8, 5.7 Hz), 8.36 (d, 1H,J=7.8 Hz), 8.65 (d, 1H, J=9.6 Hz); ¹³C NMR (D₂O) δ 20.40, 23.75, 27.69,29.09, 48.45, 50.79, 60.42, 114.20, 125.88, 126.99, 130.98, 139.35,140.72, 148.06, 151.35, 151.79, 152.94. ES-MS m/z405 (M+H). Anal. Calcd.for C₂₂H₂₈N₈.3.1HBr.1.4H₂O.0.4C₄H₁₀O: C, 39.91; H, 5.38; N, 15.78; Br,34.88. Found C, 39.89; H, 5.29; N, 15.84; Br, 34.94.

Example 26

COMPOUND 26: Preparation of1-N′-[4-(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-aminobutane-N,N-dimethylformamidine(hydrobromide salt)

Using the procedure of L. Cai (Y. Han and L. Cai Tetrahedron Lett. 1997,38(31), 5423-5426) a solution of 2-pyridinesulfonyl chloride (56 mg,0.32 mmol) in DMF (1 mL) was stirred for 10 minutes at room temperature.N′-(1H-Benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(73 mg, 0.21 mmol) was then added, and the mixture was stirred at roomtemperature for 2 hours. The DMF was then removed in vacuo, and theresidue was taken up in dichloromethane and washed sequentially with asaturated aqueous sodium carbonate solution, followed by distilledwater. The organic fraction was then dried over anhydrous sodium sulfateand concentrated. The residue was then purified by silica gel flashchromatography to afford two products:1-N′-[4-(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amnino]-aminobutane-N,N-dinethylformamidine(51 mg, 59%), andN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine-N-(2-pyridinyl)-sulfonamide(31 mg, 29%). The spectral data for the fonnamidine is as follows: ¹HNMR (CDCl₃) δ 1.38-1.44 (m, 4H), 1.68 (m, 1H), 2.00 (m, 1H), 2.15 (m,1H), 2.35 (m, 1H), 2.66-3.01 (m, 4H), 3.01 (s, 6H), 3.16 (t, 2H, J=6.9Hz), 4.05 (s, 2H), 4.12 (m, 1H), 7.18 (m, 2H), 7.46 (m, 1H), 7.58 (m,2H), 8.53 (m, 1H). The sulfonamide showed an excessive broadening ofresonances in the ¹H NMR spectrum (in CDCl₃), so it was notcharacterized fully at this stage, and was instead taken directly to thesalting reaction.

1-N′-[4-(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-aminobutane-N,N-dimethylformamidine(49 mg, 0.120 mmol) was taken up in acetic acid (1 mL), to which asaturated solution of HBr in acetic acid (1 mL) was added. The mixturewas then stirred, precipitated and isolated as per procedure D to yieldCOMPOUND 26 as a white crystalline solid (52 mg). ¹H NMR (D₂O). δ 1.39(m, 4H), 1.85 (m, 1H), 2.01 (m, 1H), 2.15 (m, 1H), 2.36 (m, 1H), 2.53(m, 1H), 2.78 (m, 1H), 2.85 (s, 3H), 3.00 (m, 2H), 3.07 (s, 3H), 3.25(t, 2H, J=6.9 Hz), 4.46 (d, 1H, J=16.8 Hz), 4.51 (m, 1H), 4.52 (d, 1H,J=16.8 Hz), 7.60 (m, 2H), 7.65 (s, 1H), 7.80 (m, 2H), 7.87 (dd, 1H,J=7.8, 5.8 Hz), 8.35 (d, 1H, J=7.8 Hz), 8.63 (d, 1H, J=5.8 Hz). ¹³C NMR(D₂O) δ 22.89, 23.27, 27.81, 30.10, 38.38, 45.57, 49.52, 51.21, 54.51,63.61, 116.70, 128.35, 129.43, 133.35, 141.73, 143.03, 150.53, 153.75,154.54, 158.63. ES-MS m/z 405 (M+H); Anal. Calcd. for (C₂₄H₃₂N₆×3.3HBr×1.8 H₂O): C, 40.95; H, 5.57; N, 11.94; Br 37.46. Found: C, 40.77; H,5.59; N, 11.78; Br, 37.72.

Example 27

COMPOUND 27: Preparation ofN-{4-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-guanidine(hydrobromide salt)

A solution ofN¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-N¹-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-ylmethyl]-butane-1,4-diamine(170 mg, 0.35 mmol), 1-H-pyrazole-1-carboxamidine hydrochloride (51 mg,0.35 mmol) and DIPEA (61 μL, 0.35 mmol) in THF (0.2 mL) was stirred atroom temperature for 3 hours. Ether (1×10 mL and 3×5 mL) was added anddecanted. The resulting syrup was dried in vacuo to afford a white foam(150 mg) that was used in the next reaction without furtherpurification.

A solution of the guanidine from above (150 mg) in 6N HC (5 mL) washeated to 50° C. for 4 hours. The reaction mixture was cooled to roomtemperature, H₂O (5 mL) was added and the mixture was neutralized withNaHCO₃ (s) and saturated with NaCl (s). The aqueous layer was extractedwith CHCl₃ (3×50 mL). The combined organic extracts were dried (MgSO₄),filtered and concentrated under reduced pressure. Purification by columnchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 20:2:1) afforded thedesired guanidine as a light yellow foam (63 mg, 46% over 2 steps).

Using General Procedure D: Conversion of the foam from above to thehydrobromide salt afforded COMPOUND 27 as a light beige solid. ¹H NMR(D₂O) δ 1.40 (br s, 4H), 1.81-1.90 (m, 1H), 1.98-2.10 (m, 2H), 2.34-2.38(m, 1H), 2.48-2.54 (m, 1H), 2.74-2.83 (m, 1H), 2.99-3.03 (m, 4H), 4.44(d, 1H, J=10.8 Hz), 4.51-4.63 (m, 2H), 7.57-7.63 (m, 2H), 7.77-7.82 (m,2H), 7.87 (dd, 1H, J=7.8, 6.0 Hz), 8.35 (d, 1H, J=8.1 Hz), 8.64 (d, 1H,J=5.5 Hz); ¹³C NMR (D₂O) δ 20.45, 25.52, 26.10, 27.66, 41.01, 48.97,51.89, 61.17, 114.27, 125.92, 126.92, 131.04, 139.29, 140.50, 148.04,151.41, 152.03, 156.91. ES-MS m/z 392.3 (M+H). Anal. Calcd. forC₂₂H₂₉N₇.3.1HBr.1.2H₂O.0.3C₄H₁₀O: C, 40.61; H, 5.51; N, 14.29; Br,36.10. Found: C, 40.92; H, 5.31; N, 14.28; Br, 35.70.

Example 28

COMPOUND 28: Preparation ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine-N-(2-pyridinyl)-sulfonamide(hydrobromide salt)

N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine-N-(2-pyridinyl)-sulfonamide(from the above reaction, 31 mg, 0.063 mmol) was taken up in acetic acid(1 mL), to which a saturated solution of HBr in acetic acid (1 mL) wasadded. The mixture was then stirred, precipitated and isolated as perprocedure D to yield COMPOUND 28 as a white crystalline solid (52 mg).¹H NMR (D₂O) δ 1.30 (m, 4H), 1.81 (m, 1H), 1.91 (m, 1H), 2.05 (m, 1H),2.31 (m, 1H), 2.43 (m, 1H), 2.79 (m, 1H), 2.83 (t, 2H, J=6.9 Hz), 3.00(m, 2H), 4.31 (d, 1H, J=16.3 Hz), 4.49 (m, 1H), 4.51 (d, 1H, J=16.3 Hz),7.57 (m, 2H), 7.86 (m, 2H), 7.83 (m, 2H), 8.00 (t, 2H, J=7.8 Hz), 8.32(d, 1H, J=7.8 Hz), 8.56 (d, 1H, J=4.9 Hz), 8.68 (d, 1H, J=5.4 Hz). ¹³CNMR (D₂O) 6 20.43, 20.81, 24.95, 26.54, 27.64, 42.44, 48.80, 51.47,60.94, 114.26, 122.86, 125.92, 126.91, 128.36, 130.97, 139.30, 140.08,140.48, 140.06, 150.22, 151.40, 152.00. ES-MS m/z 491 (M+H); Anal.Calcd. for (C₂₆H₃₀N₆O₂S×3.1 HBr×1.7 H₂O×0.9 HOAc): C, 40.42; H, 4.89; N,10.17; Br 29.98. Found: C, 40.31; H, 4.98; N, 10.13; Br, 30.22.

Example 29

COMPOUND 29: Preparation ofN-(1H-benzoimidazol-2-ylmethyl)-N′-pyrimidin-2-ylmethyl-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

Pyrimidine-2-carbaldehyde was prepared as described for COMPOUND 68using pyrimidine-2-carboxylic acid methyl ester (255 mg, 1.85 mmol), THF(18 mL), and LiAlH₄ (1.0 M/THF, 0.55 mL, 0.55 mmol). The crude material(332 mg) was determined by ¹H NMR to be a mixture ofpyrimidine-2-carbaldehyde, pyrimidine-2-carboxylic acid methyl ester,and THF (1.0:12.6:6.0 respectively) and was used in the next stepwithout further purification.

Using General Procedure B: To a solution of the crude aldehyde fromabove (332 mg) andN′-(1H-benzoimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(49 mg, 0.14 mmol) in THF (2 mL) was added NaBH(OAc)₃ (89 mg, 0.42 mmol)and the mixture was stirred at room temperature for 1.5 h. The crudematerial was dissolved in saturated HBr/AcOH (2 mL) and stirred at roomtemperature for 5 minutes. The solution was made basic with 10 NNaOH(aq) and extracted with CH₂Cl₂ (3×15 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. Purification ofthe crude material by column chromatography on silica gel (200:5:1CH₂Cl₂/MeOH/NH₄OH) afforded a yellow oil (44 mg).

Using General Procedure D: Conversion of the oil from above (44 mg, 0.10mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 29 (68 mg, 84%) asa colourless solid. ¹H NMR (D₂O) δ 1.64-1.93 (m, 5H), 2.07 (m, 1H), 2.22(m, 1H), 2.42 (m, 1H), 2.61 (m, 1H), 2.89 (m, 1H), 3.04 (m, 2H), 3.15(m, 2H), 4.41-4.61 (m, 5H), 7.53 (t, 1H, J=5.1 Hz), 7.63 (m, 2H), 7.87(m, 3H), 8.38 (d, 1H, J=8.1 Hz), 8.67 (d, 1H, J=5.7 Hz), 8.80 (d, 2H,J=5.1 Hz); ¹³C NMR (D₂O) δ 20.44, 23.80, 25.46, 27.66, 47.61, 48.30,51.00, 51.68, 60.67, 114.27, 121.65, 125.94, 126.94, 130.95, 139.35,140.62, 148.12, 151.24, 151.78, 158.37, 160.71. ES-MS m/z 442 (M+H).Anal. Calcd. for C₂₆H₃₁N₇.4.0HBr.3.2H₂O: C, 37.95; H, 5.07; N, 11.92;Br, 38.84. Found: C, 38.20; H, 5.04; N, 11.77; Br, 38.61.

Example 30

COMPOUND 30: Preparation ofN-(1H-benzoimidazol-2-ylmethyl)-N′-(1H-imidazol-2-yl)-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

To a partially dissolved solution of 2-aminoimidazole sulfate (200 mg,1.51 mmol) in MeOH (2 mL) was added NaOH (s) (65 mg, 1.59 mmol) and themixture was stirred at room temperature overnight. The mixture wasdiluted with CH₂Cl₂ (20 mL), dried (MgSO4) and filtered through Celite.The cake was washed with CH₂Cl₂/MeOH (10:1) and the filtrate wasconcentrated under reduced pressure to afford a brown syrup (115 mg)that was used in the next reaction without further purification.

A solution of the amine from above (39 mg, 0.47 mmol) and4-{[1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino}butyraldehyde(see COMPOUND 32 for preparation) (100 mg, 0.22 mmol) in MeOH (1.5 mL)was stirred at 40° C. for 3 days. NaBH₄ (17 mg, 0.44 mmol) was added andthe resultant mixture stirred for an additional 15 minutes. The reactionmixture was diluted with CH₂Cl₂, filtered through Celite and the cakewas washed with CH₂Cl₂. The combined filtrate was concentrated underreduced pressure. Purification of the crude orange foam by columnchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 50:2:1) followed byradial chromatography on silica gel (1 mm plate, EtOAc/MeOH/NH₄OH,100:3:1) afforded COMPOUND 30 (32 mg, 35%) as a light purple foam. ¹HNMR (CDCl₃) δ 1.32-1.75 (m, 5H), 1.83-1.95 (m, 1H), 2.02-2.10 (m, 1H),2.17-2.21 (m, 1H), 2.51-2.91 (m, 4H), 3.05-3.09 (m, 2H), 3.98-4.11 (m,3H), 4.31 (br s, 1H), 6.61 (s, 2H), 7.12-7.16 (m, 1H), 7.18-7.23 (m,2H), 7.43 (d, 1H, J=7.2 Hz), 7.56 (br s, 2H), 8.52 (d, 1H, J=3.3 Hz);¹³C NMR (CDCl₃) δ 21.12, 23.92, 25.24, 27.29, 29.14, 43.55, 49.17,50.22, 62.13, 114.93, 117.27, 121.89, 122.34, 134.91, 137.65, 146.48,150.88, 156.09, 157.26. ES-MS m/z 416.3 (M+H). Anal. Calcd. forC₂₄H₂₉N₇.0.9H₂O.0.3C₄H₈O₂: C, 66.06; H, 7.30; N, 21.40. Found: C, 66.12;H, 7.32; N, 21.34.

Example 31

COMPOUND 31: Preparation ofN¹-(1H-benzimidazol-2-ylmethyl)-N⁴-(1H-indol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine

A solution of indole-2-carboxaldehyde (prepared as described forCOMPOUND 65) (31 mg, 0.21 mmol) andN¹-(1H-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine(see COMPOUND 17) (51 mg, 0.15 mmol) in MeOH (1.8 mL) was stirred atroom temperature under nitrogen for 23 hours. NaBH₄ (14 mg, 0.37 mmol)was added, and the reaction stirred for a further 15 minutes before thesolvent was evaporated under reduced pressure. The residue was dissolvedinto CH₂Cl₂ (25 mL) and was washed with saturated aqueous NaHCO₃ (5 mL)and brine (5 mL). The organic solution was dried (MgSO₄), filtered andevaporated under reduced pressure. The yellow residue was purified byflash column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1)giving COMPOUND 31 as a white solid (37 mg, 0.077 mmol, 53%). ¹H NMR(CDCl₃) δ 1.35-1.49 (m, 4H), 1.60-1.76 (m, 1H), 1.81-1.96 (m, 1H),1.96-2.08 (m, 1H), 2.11-2.22 (m, 1H), 2.45 (t, 2H, J=6.5 Hz), 2.50-2.60(m, 1H), 2.66-2.76 (m, 2H), 2.76-2.90 (m, 1H), 3.83 (s, 2H), 3.93-4.10(m, 3H), 6.27 (s, 1H), 7.02-7.16 (m, 3H), 7.16-7.24 (m, 2H), 7.32 (d,1H, J=7.8 Hz), 7.41 (d, 1H, J=7.8 Hz), 7.53 (d, 1H, J=7.8 Hz), 7.55-7.62(m, 2H), 8.56 (d, 1H, J=3.6 Hz), 9.01 (br. s, 1H). ¹³C NMR (CDCl₃) δ21.6, 23.8, 26.2, 27.5, 29.6, 47.2, 48.9, 49.8, 50.8, 62.3, 100.6,111.2, 119.8, 120.4, 121.7, 122.0, 122.6, 128.8, 135.1, 136.5, 137.8,147.1, 156.9, 157.8. ES-MS m/z 479 (M+H). Anal. Calcd. forC₃₀H₃₄N₆.0.5CH₂Cl₂.0.2C₄H₁₀O: C, 70.15; H, 6.96; N, 15.68. Found: C,70.16; H, 6.97; N, 15.73.

Example 32

COMPOUND 32: (1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(N,N-dimethyl-4-amino-but-1-yl)-amine(Hydrobromide salt) Preparation of[1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-(4-hydroxy-but-1-yl)-amine

To a stirred suspension of NaH (95%, 0.81 g, 33.8 mmol) in THF (68 mL)at room temperature was added 1,4-butanediol (3.0 mL, 33.9 mmol). After1.5 hours, tert-butyldimethylsilyl chloride (5.14 g, 34.1 mmol) wasadded. After stirring for a further 2.5 hours, the reaction was dilutedwith diethyl ether (250 mL). The organic phase was washed with saturatedaqueous NaHCO₃ (2×75 mL) and brine (1×75 mL). The combined aqueousphases were extracted with ether (1×75 mL). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated under reducedpressure to give a colourless liquid (6.40 g, 92%).

To a stirred solution of oxalyl chloride (6.0 mL, 68.8 mmol) in CH₂Cl₂(450 mL) at −78° C. was added DMSO (6.5 mL, 91.6 mmol). After 2 hours,the alcohol from above (6.40 g, 31.3 mmol) was added as a solution inCH₂Cl₂ (90 mL). Triethylamine (32 mL, 230 mmol) was added after 20minutes, followed by removal of the ice bath. After 1 hour the reactionwas washed with water (1×200 mL). The aqueous phase was extracted withCH₂Cl₂ (3×100 mL). The combined organic phase was washed with 1N HCl(1×200 mL), saturated aqueous NaHCO₃ (1×200 mL) and brine (1×200 mL).The organic phase was dried (Na₂SO₄), filtered and concentrated underreduced pressure to give 6.36 g of a yellow liquid (quantitative).

Using the General Procedure B: To a stirred solution of the aldehdyefrom above (3.085 g, 15.2 mmol) and(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(3.67 g, 13.2 mmol) in CH₂Cl₂ (90 mL) was added NaBH(OAc)₃ (6.33 g, 29.9mmol) and the mixture stirred for 16 hours. The yellow foam obtained(8.06 g) was dissolved in THF (20 mL) and treated with 3N HCl (80 mL).After 2 hours, the reaction was basified with saturated aqueous NaHCO₃.The phases were separated, and the aqueous phase was extracted withdiethyl ether (4×150 mL) and CH₂Cl₂ (2×150 mL). The organic phase wasdried (Na₂SO₄), filtered and concentrated under reduced pressure to givean orange oil (4.44 g, 72%).

To a stirred solution of the protected alcohol from above (5.01 g, 10.8mmol) in THF (50 mL) at 0° C. was added hydrogen fluoride-pyridine (˜5mL, ˜175 mmol). After 75 minutes, a further 1 mL of HF-pyridine wasadded. After a further 20 minutes, the pH of the solution was raised topH 13 with 1N NaOH followed by 10N NaOH. The mixture was extracted withCH₂Cl₂ (5×40 mL). The organic phase was dried (Na₂SO₄), filtered andconcentrated under reduced pressure to give a crude oil (4.22 g).Purification of this oil by column chromatography (4 cm OD, 100 gsilica, 30:1 CH₂Cl₂:CH₃OH) afforded the deprotected alcohol as a yellowfoam (2.92 g, 77%).

To a stirred solution of the deprotected alcohol from above (2.92 g,8.33 mmol) and diisopropylethyl amine (15 drops) in THF (40 mL) at 0° C.was added di-tert-butyl di-carbonate (1.96 g, 8.98 mmol). After stirringfor 17 hours (over which time the reaction warmed to room temperature),the reaction was concentrated under reduced pressure. The residue wasdissolved in CH₂Cl₂ (100 mL) and washed with brine (3×50 mL). Theorganic phase was dried (Na₂SO₄), filtered and concentrated underreduced pressure to afford the N-protected material as a crude yellowfoam (3.79 g, quantitative). ¹H NMR (CDCl₃) δ 1.48-1.71 (m, 14H),1.93-2.05 (m, 2H), 2.15-2.25 (m, 1H), 2.57-2.67 (m, 1H), 2.71-2.94 (m,3H), 2.53-2.59 (m, 2H), 4.32 (dd, 1H, J=9.7, 6.5 Hz), 4.49 (d, 1H,J=15.8 Hz), 4.61 (d, 1H, J=15.8 Hz), 6.93 (dd, 1H, J=7.7, 4.6 Hz),7.20-7.30 (m, 3H), 7.68-7.72 (m, 1H), 7.78-7.83 (m, 1H), 8.33 (d, 1H,J=3.7 Hz).

Preparation of4-{[1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino}butyraldehyde

To a stirred solution of oxalyl chloride (4.5 mL, 9.0 mmol) in CH₂Cl₂(40 mL) at −78° C. was added DMSO (0.86 mL, 12.1 mmol). After 30 minutes[1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-(4-hydroxy-but-1-yl)-amine(3.66 g, 8.13 mmol) was added as a solution in CH₂Cl₂ (7.5 mL). After afurther 20 minutes, triethylamine (70 mL, 71.7 mmol) was added and theice bath was removed. The reaction was stirred for a further 75 minutesthen concentrated under reduced pressure. The residue was taken up inethyl acetate and filtered through celite to give a crude yellow oil(3.88 g). Purification of this oil by column chromatography on silicagel (solvent=35:1:1 CH₂Cl₂:CH₃OH:NH₄OH) afforded the desired purealdehyde (1.25 g, 39%). ¹H NMR (CDCl₃) δ 1.52-1.72 (m, 13H), 1.74-1.88(m, 1H), 1.90-2.00 (m, 1H), 2.06-2.17 (m, 1H), 2.36 (t, 2H, J=6.6 Hz),2.53-2.74 (m, 2H), 2.79-2.88 (m, 1H), 4.22 (dd, 1H, J=9.7, 6.3 Hz), 4.48(d, 1H, J=15.4 Hz), 4.66 (d, 1H, J=15.2 Hz), 6.93 (dd, 1H, J=7.6, 4.7Hz), 7.19-7.28 (m, 4H), 7.65-7.70 (m, 1H), 7.73-7.82 (m, 1H), 8.33 (d,1H, J=3.6 Hz), 9.56 (s, 1H).

Using the General Procedure B: To a stirred solution of4-{[1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino}butyraldehyde(119 mg, 0.265 mmol) and dimethyl amine (2.0M in THF, 0.145 mL, 0.290mmol) in THF (5 mL) was added NaBH(OAc)₃ (84 mg, 0.396 mmol) and themixture stirred for 17 hours. Purification of the crude orange oil (116mg) by radial chromatography on silica gel (75:1:1 CH₂Cl₂:CH₃OH:NH₄OH)afforded the desired N-protected intermediate (69 mg, 55%).

Using the General Procedure D for simultaneous Deprotection and HBrsalting: Conversion of the N-protected material from above (69 mg) tothe hydrobromide salt was afforded a white solid (80 mg). This solid wasdiluted with 10N NaOH (3 mL) and extracted with CH₂Cl₂ (5×3 mL). Theorganic phase was dried (Na₂SO₄), filtered and concentrated underreduced pressure. Purification of the yellow oil (40 mg) obtained byradial chromatography on silica gel (60:1:1 CH₂Cl₂:CH₃OH:NH₄OH) affordedthe pure freebase as a colourless oil (19 mg, 35%)

Using the General Procedure D: Conversion of the freebase from above (19mg) to the hydrobromide salt gave COMPOUND 32 as a white solid (24 mg,71%). ¹H NMR (D₂O) δ 1.46-1.64 (m, 4H), 1.77-1.90 (m, 1H), 1.95-2.09 (m,1H), 2.13-2.23 (m, 1H), 2.51-2.62 (m, 1H), 2.74-2.89 (m, 7H) containing2.81 (s, 6H), 2.96-3.03 (m, 4H), 4.39 (d, 1H, J=16.6 Hz), 4.48-4.58 (m,2H) containing 4.53 (d, 1H, J=17.1 Hz), 7.61 (dd, 2H, J=6.2, 3.1 Hz),7.81 (dd, 2H, J=6.2, 3.2 Hz), 7.87 (dd, 1H, J=6.7, 6.9 Hz), 8.35 (d, 1H,J=7.9 Hz), 8.63 (d, 1H, J=5.4 Hz). ¹³C NMR (D₂O) δ 20.43 (2 carbons),22.27, 25.33, 27.63, 43.02 (2 carbons), 48.23, 51.66, 57.62, 60.70,114.25 (2 carbons), 125.93, 126.93 (2 carbons), 131.01, 139.31, 140.60,148.10, 151.24, 151.76. ES-MS m/z 378 (M+H) Anal Calc. for C₂₃H₃₁N₅.3.0HBr.3.1H₂O: C, 40.86; H, 5.99; N, 10.36; Br, 35.45. Found: C, 40.74;H, 5.91; N, 10.22; Br, 35.71.

Example 33

COMPOUND 33:(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(N-allyl-4-amino-but-1-yl)-amine

4-Bromo-butan-1-ol (1.30 mL, 11.8 mmol) was added dropwise to refluxingallylamine (2.05 g, 35.9 mmol) and the mixture was stirred at 65° C. for23 hours. The orange solution was diluted with 10N NaOH (15 mL) anddiethyl ether (30 mL). The aqueous phase was subsequently extracted withether (2×30 mL). The organic phase was dried (MgSO₄), filtered andconcentrated under reduced pressure to give a yellow oil (841 mg, 55%).

To a stirred solution of the secondary amine from above (841 mg, 6.51mmol) in THF at 0° C. was added di-tert-butyl di-carbonate (1.449 g,6.64 mmol) and the reaction was stirred at 0° C. for 2 hours. Thereaction was concentrated under reduced pressure. The yellow oil (1.645g) was purified by column chromatography (4 cm OD, 35 g silica, EtOAc)to afford the N-protected alcohol (1.246 g, 84%).

To a suspension of the N-protected alcohol from above (236 mg, 1.03mmol), NMO (187 mg, 1.59 mmol) and 3 Å molecular sieves (537 mg) inCH₂Cl₂ (5 mL) was added TPAP (37 mg, 0.106 mmol) and the mixture wasstirred at room temperature for 2 hours. The mixture was filteredthrough a silica gel plug with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The yellow oil (197 mg) waspurified by column chromatography (12 g silica, 10:1 hexanes:ethylacetate) to give the N-protected aldehyde (112 mg, 48%).

Using the General Procedure B: To a stirred solution of the N-protectedaldehyde from above (112 mg, 0.49 mmol) and[1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(187 mg, 0.49 mmol) in CH₂Cl₂ (5 mL) was added NaBH(OAc)₃ (208 mg, 0.98mmol) and the mixture was stirred for 17 hours. Purification of thecrude yellow oil (286 mg) by flash chromatography (12 g silica, 50:1:1CH₂Cl₂:CH₃OH:NH₄OH) afforded the N-protected tertiary amine (172 mg,59%).

Using the General Procedure D: the N-protected tertiary amine from above(172 mg, 0.308 mmol) was converted to COMPOUND 33 as a white solid (145mg, 70%). ¹H NMR (D₂O) δ 1.53 (br s, 4H), 1.77-1.90 (m, 1H), 1.95-2.03(m, 1H), 2.13-2.23 (m, 1H), 2.32-2.42 (m, 1H), 2.50-2.60 (m, 1H),2.77-2.86 (m, 1H), 2.88-2.95 (m, 2H), 2.97-3.03 (m, 2H), 3.56 (d, 2H,J=6.5 Hz), 4.38 (d, 1H, J=16.7 Hz), 4.47-4.56 (m, 2H) containing 4.53(d, 1H, J=17.0 Hz), 5.39 (s, 1H), 5.44 (d, 1H, J=4.8 Hz), 5.74-5.89 (m,1H), 7.60 (dd, 2H, J=6.1, 3.0 Hz), 7.80 (dd, 2H, J=6.4, 3.4 Hz), 7.86(dd, 1H, J=7.9, 5.8 Hz), 8.34 (d, 1H, J=7.9 Hz), 8.62 (d, 1H, J=5.3 Hz).¹³C NMR (D₂O) δ 19.81 (2 carbons), 20.42, 23.79, 25.47, 27.28, 27.63,46.75, 48.23, 49.80, 51.65, 50.65, 114.25 (2 carbons), 124.01, 125.93,126.94 (2 carbons), 127.70, 130.98, 139.31, 140.61, 148.10, 151.26,151.78. ES-MS m/z390 (M+H) Anal Calc. for C₂₁H₂₅N₅O.3.2HBr.1.9H₂O: C,38.41; H, 4.91; N, 10.67; Br, 38.94. Found: C, 38.53; H, 5.02; N, 10.42;Br, 38.79.

Example 34

COMPOUND 34:(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(N-methyl-4-amino-but-1-yl)-amine

To a stirred solution of 4-(methylamino)-butyric acid hydrochloride (303mg, 1.97 mmol) and dioxane (2 mL) in saturated aqueous NaHCO₃ (2 mL) wasadded added di-tert-butyl di-carbonate (523 mg, 2.40 mmol) and themixture was stirred at 0° C. for 20 minutes followed by stirring at roomtemperature for 22 hours. The reaction was concentrated under reducedpressure and the residue was diluted with water (20 mL). The aqueousphase was extracted with ethyl acetate (2×15 mL). The aqueous phase wastreated with 5% w/v aqueous citric acid until a pH of 4 was obtained.The aqueous phase was then again extracted with ethyl acetate (4×15 mL).The combined organic phase was dried (MgSO₄), filtered and concentratedunder reduced pressure to give a colourless oil (300 mg, 70%).

To a stirred solution of the N-protected acid from above (143 mg, 0.659mmol) in THF (5 mL) was added BH₃.THF (1.0M in THF, 2.5 mmol) and themixture was stirred at 50° C. for 64 hours. Dry CH₃OH (5 mL) was added,and the mixture stirred at 70° C. for 1 hour. The reaction wasconcentrated under reduced pressure. The crude yellow oil (148 mg) waspurified by column chromatography (2 cm OD, 20 g silica, 1:1EtOAc:hexanes) to afford the N-protected alcohol (71 mg, 53%).

To a suspension of the N-protected alcohol from above (71 mg, 0.35mmol), NMO (65 mg, 0.56 mmol) and 3 Å molecular sieves (186 mg) inCH₂Cl₂ (2.55 mL) was added TPAP (13 mg, 0.04 mmol) and the mixture wasstirred at room temperature for 1 hour. The mixture was filtered througha silica gel plug with ethyl acetate. The filtrate was concentratedunder reduced pressure to give a yellow oil (46 mg, 65%).

Using the General Procedure B: To a stirred solution of the N-protectedaldehyde from above (46 mg, 0.229 mmol) and[1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(89 mg, 0.229 mmol) in CH₂Cl₂ (2.55 mL) was added NaBH(OAc)₃ (100 mg,0.47 mmol) and the mixture was stirred for 19 hours. Purification of thecrude yellow oil (126 mg) by flash chromatography (12 g silica, 50:1:1CH₂Cl₂:CH₃OH:NH₄OH) afforded the N-protected tertiary amine (80 mg,62%).

Using the General Procedure D: The N-protected tertiary amine from above(76 mg, 0.135 mmol) was converted to COMPOUND 34 as a white solid (71mg, 75%). ¹H NMR (D₂O) δ 1.54 (br s, 4H), 1.74-1.90 (m, 1H), 1.95-2.09(m, 1H), 2.13-2.23 (m, 1H), 2.50-2.64 (m, 4H) containing 2.61 (s, 3H),2.77-2.94 (m, 3H), 2.97-3.04 (m, 2H), 4.39 (d, 1H, J=17.1 Hz), 4.47-4.60(m, 2H) containing 4.53 (d, 1H, J=17.2 Hz), 7.60 (dd, 2H, J=6.1, 3.0Hz), 7.80 (dd, 2H, J=6.1, 3.0 Hz), 7.86 (dd, 1H, J=7.9, 6.2 Hz), 8.34(d, 1H, J=7.9 Hz), 8.62 (d, 1H, J=5.0 Hz). ¹³C NMR (D₂O) δ 20.42 (2carbons), 23.69, 25.40, 27.64, 33.05, 48.23, 49.00, 51.68, 60.66, 114.25(2 carbons), 125.93, 126.93 (2 carbons), 130.97, 139.31, 140.61, 148.10,151.25, 151.77. ES-MS m/z 364 (M+H). Anal Calc. forC₂₁H₂₅N₅O.3.2HBr.1.9H₂O: C, 38.41; H, 4.91; N, 10.67; Br, 38.94. Found:C, 38.53; H, 5.02; N, 10.42; Br, 38.79.

Example 35

COMPOUND 35: Preparation of(1H-benzimidazol-2-ylmethyl)-[3-(2H-pyrazol-3-yl-propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (hydrobromide salt)Preparation of (cyanomethyl)triphenylphosphonium bromide

To a solution of PPh₃ (1.57 g, 5.99 mmol) in Et₂O (30 mL) was addedBrCH₂CN (0.42 mL, 6.0 mmol). The reaction was stirred at reflux for 17hours. The solvent was removed under reduced pressure, the residue wassuction filtered from a small portion of ice-cold Et₂O, and washed witha small amount of cold Et₂O, giving the phosphonium salt as a whitepowder (1.05 g, 2.74 mmol, 46%). ¹H NMR (CDCl₃) δ 6.39 (d, 2H, J=15.3Hz), 7.69-7.76 (m, 6H), 7.82-7.87 (m, 3H), 7.96-8.03 (m, 6H).

Preparation of 3-(2H-pyrazol-3-yl)-acrylonitrile

To a suspension of the phosphonium salt (900 mg, 2.35 mmol) in THF (10mL) under nitrogen was added NaH (60% in mineral oil, 99 mg, 2.5 mmol)in one portion. The suspension stirred at room temperature for 10minutes, then pyrazole-3-carboxaldehyde (211 mg, 2.20 mmol) was added asa solid in one portion. The reaction was heated to reflux for 30minutes, then cooled to room temperature and saturated aqueous NH₄Cl (10mL) was added. The mixture was extracted with CH₂Cl₂ (25 mL×3) and thecombined organic solution was dried (MgSO₄), filtered and concentratedunder reduced pressure. Purification by flash column chromatography onsilica (EtOAc/hexane, 1:1) gave the alkene (white solid) as anapproximately 1.5:1 mixture of the E:Z isomers (232 mg, 1.95 mmol, 89%).

Data for E-isomer: ¹H NMR (CDCl₃) δ 5.92 (d, 1H, J=16.5 Hz), 6.54 (d,1H, J=2.4 Hz), 7.43 (d, 1H, J=16.8 Hz), 7.60 (d, 1H, J=2.4 Hz).

Data for Z-isomer: ¹H NMR (CDCl₃) δ 5.46 (d, 1H, J=12.0 Hz), 6.98 (d,1H, J=2.4 Hz), 7.24 (d, 1H, J=12.3 Hz), 7.66 (d, 1H, J=2.4 Hz).

Preparation of 3-(2H-pyrazol-3-yl)-propylamine

The α,β-unsaturated nitrile (mixture of isomers, 250 mg, 2.10 mmol) washydrogenated (45 psi) over Raney-nickel in MeOH saturated with NH3 (15mL) for 15.5 hours. The mixture was suction filtered through Celite andwashed with MeOH. The filtrate was concentrated under reduced pressuregiving a brown oil. Purification by flash column chromatography onsilica (CH₂Cl₂/MeOH/NH₄OH, 5.6:1:0.07) gave the saturated primary amineas a yellow oil (197 mg, 1.57 mmol, 75%). ¹H NMR (CDCl₃) δ 1.82 (quint,2H, J=7.1 Hz), 2.76 (apparent q, 4H, J=6.8 Hz), 4.46 (br. s, 3H), 6.07(d, 1H, J=2.1 Hz), 7.47 (d, 1H, J=1.8 Hz).

Preparation of[3-(2H-pyrazol-3-yl)-propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

A solution of the primary amine (190 mg, 1.52 mmol) and8-oxo-5,6,7,8-tetrahydroquinoline (270 mg, 1.83 mmol) in MeOH (4 mL) wasstirred at room temperature for 6 hours. NaBH₄ (75 mg, 2.0 mmol) wasadded and the reaction was stirred for an additional 15 minutes, thenthe solvent was evaporated under reduced pressure. The residue was takenup into CH₂Cl₂ (20 mL) and was washed with saturated aqueous NaHCO₃ (5mL) and brine (5 mL). The organic solution was dried (MgSO₄), filteredand concentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1, then MeOH) gavethe secondary amine as a yellow oil (100 mg, 0.39 mmol, 26%). ¹H NMR(CDCl₃) δ 1.67-1.87 (m, 2H), 1.90-2.03 (m, 3H), 2.11-2.23 (m, 1H),2.67-2.89 (m, 6H), 3.84 (dd, 1H, J=7.7, 5.3 Hz), 6.03 (d, 1H, J=1.8 Hz),7.09 (dd, 1H, J=7.7, 4.7 Hz), 7.39 (d, 1H, J=7.6 Hz), 7.41 (d, 1H, J=1.8Hz), 8.42 (d, 1H, J=3.9 Hz). cl Preparation of2-{[[3-(2H-pyrazol-3-yl)-propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester

A solution of the amine (100 mg, 0.39 mmol), tert-butyl2-chloromethyl-benzimidazole-1-carboxylate (107 mg, 0.40 mmol), DIPEA(0.10 mL, 0.57 mmol) and KI (approx. 10 mg) in CH₃CN (2.5 mL) was heatedto 60° C. under nitrogen for 18.5 hours. Once cooled to roomtemperature, saturated aqueous NaHCO₃ (10 mL) was added and the mixturewas extracted with CH₂Cl₂ (15 mL×3). The combined organic solution wasdried (MgSO₄), filtered and concentrated under reduced pressure. Threeattempts at purification by flash column chromatography on silica, thefirst eluted with CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1, the second eluted withCH₂Cl₂/MeOH/NH₄OH, 49:1:0.25, gradually increased to 19:1:0.1, and thethird eluted with CH₂Cl_(2/)MeOH/NH₄OH, 49:1:0.25, gave the tertiaryamine as a white foam (70.6 mg, 0.15 mmol, 37%¹). ¹H NMR (CDCl₃) δ 1.64(s, 9H), 1.64-1.80 (m, 2H), 1.90-2.12 (m, 3H), 2.19-2.33 (m, 1H),2.41-2.51 (m, 1H), 2.60-2.86 (m, 4H), 3.06-3.15 (m, 1H), 3.23-3.37 (m,1H), 4.04 (dd, 1H, J=10.4, 6.8 Hz), 4.19 (d, 1H, J=15.0 Hz), 4.53 (d,1H, J=15.0 Hz), 6.00 (d, 1H, J=1.5 Hz), 6.72 (dd, 1H, J=7.5, 4.8 Hz),6.89 (d, 1H, J=7.5 Hz), 7.14-7.29 (m, 2H), 7.45 (d, 1H, J=1.5 Hz), 7.63(dd, 1H, J=7.9, 1.5 Hz), 7.73 (dd, 1H, J=7.9, 1.5 Hz), 8.35 (d, 1H,J=3.6 Hz).

Preparation of COMPOUND 35

To a solution of the tertiary amine (30.8 mg, 0.063 mmol) in glacialHOAc (1.0 mL) was added a saturated solution of HBr in HOAc (0.5 mL).The mixture was stirred at room temperature for 1 hour, then was dilutedwith Et₂O (5 mL). The solvent was decanted and the precipitate waswashed with Et₂O (1 mL×5) and dried at 90° C. under reduced pressuregiving COMPOUND 35 as a yellow solid (35.5 mg, 0.049 mmol, 78%). ¹H NMR(D₂O) δ 1.68-2.00 (m, 4H), 2.07-2.19 (m, 1H), 2.27-2.49 (m, 2H), 2.66(t, 1H, J=7.4 Hz), 2.73-2.85 (m, 1H), 2.92-3.01 (m, 2H), 4.32 (d, 1H,J=16.8 Hz), 4.47 (d, 1H, J=16.8 Hz), 4.49 (dd, 1H, J=10.7, 5.9 Hz), 6.32(d, 1H, J=2.7 Hz), 7.54-7.61 (m, 2H), 7.71-7.79 (m, 3H), 7.83 (dd, 1H,J=8.1, 5.4 Hz), 8.32 (d, 1H, J=7.8 Hz), 8.59 (d, 1H, J=5.7 Hz). ¹³C NMR(D₂O) δ 20.4, 20.5, 22.8, 27.1, 27.6, 48.1, 50.9, 60.5, 106.2, 114.2,125.9, 127.0, 130.9, 134.4, 139.3, 140.7, 148.1, 149.0, 151.1, 151.5.ES-MS nm/z 387 (M+H). Anal. Calcd. for C₂₃H₂₆N₆.3.3HBr.1.9H₂O.0.9C₄H₁₀O:C, 40.85; H, 5.10; N, 11.53; Br, 36.16. Found: C, 41.02; H, 5.05; N,11.56; Br, 35.98.

Example 36

COMPOUND 36:N′-(1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione

4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (617 mg, 2.84mmol), 6,7-dihydro-5H-quinolin-8-one (463 mg, 3.13 mmol), and sodiumtriacetoxyborohydride (1.81 g, 8.53 mmol) in CH₂Cl₂ (25 mL) were stirredat room temperature for 2 hours. Then it was quenched with 1N NaOH (20mL) and the mixture was washed with CH₂Cl₂ (2×25 mL). The organic layerwas dried (MgSO₄), filtered, concentrated, and dried in vacuo to afforda brown oil. Purification by flash column chromatography on silica gelusing CH₃OH/CH₂Cl₂ (5:95) afforded the product pure as a yellow oil (506mg, 51%). ¹H NMR (CDCl₃) δ 1.59-1.83 (m, 6H), 1.98-2.00 (m, 1H),2.14-2.16 (m, 1H), 2.73-2.81 (m, 4H), 3.70-3.76 (m, 1H), 7.06 (dd, 1H,J=6.0, 3.0 Hz), 7.36 (d, 1H, J=6.0 Hz), 7.68-7.71 (m, 2H), 7.82-7.84 (m,2H), 8.36 (d, 1H, J=6.0 Hz).

Preparation ofN′-(1H-imidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

The above amine (215 mg, 0.62 mmol), 2-imidazolecarboxaldehyde (118 mg,1.23 mmol), and sodium cyanoborohydride (114 mg, 1.85 mmol) were stirredin methanol (5 mL) overnight. Then the reaction mixture was dissolved inCH₂Cl₂ (15 mL) and extracted with saturated NaHCO₃ (3×10 mL). Theaqueous layer was washed with CH₂Cl₂ (2×20 mL). Then the combinedorganic extracts were dried (MgSO₄), filtered, concentrated, and driedin vacuo to afford a yellow foam. Purification by radial chromatographyon silica gel (2 mm plate, using NH₄OH/CH₃OH/CH₂Cl₂; 1:1:100→1:3:100)afforded the product partially clean as a yellow foam (179 mg, 67%). ¹HNMR (CDCl₃) δ 1.36-1.41 (m, 3H), 1.55-1.63 (m, 3H), 2.00-2.04 (m, 2H),2.52-2.76 (m, 4H), 3.46-3.79 (m, 2H), 3.83 (q, 2H, J=18 Hz), 4.18 (m,1H), 3.96 (s, 1H), 7.03-7.10 (m, 1H), 7.05 (s, 1H), 7.45-7.49 (m, 1H),7.67-7.71 (m, 2H), 7.79-7.81 (m 2H), 8.48 (d, 3.0 Hz).

To a solution of the above amine (179 mg, 0.42 mmol) in ethanol (4 mL)was added hydrazine hydrate (0.12 mL, 2.49 mmol). The reaction mixturewas stirred at room temperature for 3 days. Then the solvent was removedunder reduced pressure and the residue was dissolved in CH₂Cl₂ andfiltered. The filtrate was concentrated to dryness to afford a yellowoil. Purification by radial chromatography on silica gel (2 mm plate,using NH₄OH/CH₃OH/CH₂Cl₂; 1:5:100→1:10:100) afforded the product as ayellow oil (66.1 mg, 53%). ¹H NMR (CDCl₃) δ 1.31-1.38 (m, 4H), 1.61-1.65(m, 1H), 1.79-1.83 (m, 1H), 1.96-2.02 (m, 1H), 2.11-2.15 (m, 1H),2.32-2.39 (m, 1H), 2.46-2.55 (m, 2H), 2.61-2.70 (m, 2H), 2.74-2.80 (m,1H), 3.78 (q, 2H), J=15.3 Hz), 3.95 (dd, 1H, J=9.3, 6.3 Hz), 6.93 (s,2H), 7.09 (dd, 1H, J=7.7, 4.5 Hz), 7.39 (d, 1H, J=7.5 Hz), 8.42 (d, 1H,J=3.9 Hz).

Preparation ofN′-(1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of the above amine (66 mg, 0.22 mmol) in acetic acid (1mL) was added a hydrobromic acid saturated acetic acid (0.5 mL). Thereaction mixture was stirred for 30 minutes and then diethyl ether wasadded until the precipitation of COMPOUND 36 was afforded as an orangeoil (22 mg, 33%). ¹H NMR (D₂O) δ 1.47-1.50 (m, 4H), 1.81-1.94 (m, 2H),2.12-2.16 (m, 1H), 2.25-2.29 (m, 1H), 2.46-2.50 (m, 1H), 2.71-2.75 (m,1H), 2.84-2.86 (m, 2H), 2.97-3.00 (m, 2H), 4.19 (q, 2H, J=19.8 Hz),4.33-4.38 (m, 1H), 7.40 (s, 2H), 7.83 (t, 1H, J=6.3 Hz), 8.31 (d, 1H,J=8.1 Hz), 8.55 (d, 1H, J=6.0 Hz). ¹³C NMR (D₂O) δ 20.19, 20.41, 25.02,25.29, 27.57, 39.53, 47.09, 49.29, 51.20, 60.10, 119.54, 125.82, 139.22,140.45, 145.32, 147.96, 151.46. ES-MS m/z 300 [M+H]⁺. Anal. Calcd. forC₁₇H₂₅N₅.3.6HBr.1.4H₂O.0.4C₂H₄—O₂; C, 33.41; H, 5.12; N, 10.84; Br,44.76. Found: C, 33.41; H, 5.12; N, 10.84; Br, 44.76.

Example 37

COMPOUND 37: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-butane-1,4-diamine

Preparation of 6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine

To a stirred solution of 2,3-cycloheptenopyridine (42.94 g, 0.292 mol)in glacial acetic acid (160 mL) at room temperature was added 30% H₂O₂(30 mL) and the resultant solution was heated to 70° C. After 6 hours,the reaction mixture was cooled to room temperature, additional H₂O₂ (30mL) was added, and the solution was heated at 70° C. overnight. Thereaction mixture was cooled to room temperature and concentrated underreduced pressure. The residue was dissolved in CHCl₃ (200 mL) andtreated with solid Na₂CO₃ (100 g). After 1 hour, the supernatant wasdecanted and the residue was washed with warm CHCl₃ (3×200 mL). Thecombined supernatants were filtered and concentrated to provide 60 g of6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 1-oxide as a yellow oil. ¹HNMR (CDCl₃) δ 1.63-1.73 (m, 4H), 1.82-1.91 (m, 2H), 2.77-2.83 (m, 2H),3.36-3.42 (m, 2H), 6.94-7.05 (m, 2H), 8.17 (d, 1H, J=6.1 Hz).

The N-oxide was dissolved in acetic anhydride (222 mL) and heated at 90°C. overnight. The mixture was cooled to room temperature andconcentrated. Distillation (Kugelrohr, bpl 10-140° C. @ 1 Torr) of theresultant oil provided 53.26 g of acetic acid6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester.

To a solution of acetic acid6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester (53.26 g, 0.259mol) in methanol (350 mL) was added K₂CO₃ (72.98 g, mol) and theresultant mixture was stirred at room temperature overnight. The mixturewas poured into water (350 mL) and extracted with CHCl₃(3×300 mL). Thecombined organic extracts were dried (Na₂SO₄), and concentrated toprovide 41.70 g of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol.

To a stirred solution of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol(41.70 g, 0.255 mol) in CH₂Cl₂ (300 mL) at 0° C. was added triethylamine(72 mL, 0.517 mol) followed by methanesulfonyl chloride (30 mL, 0.388mol). The resultant mixture was stirred at room temperature over night.The mixture was poured into water (200 mL) and the phases wereseparated. The organic phase was washed with brine (2×150 mL), dried(Na₂SO₄), and concentrated to give 50.87 g of crude methanesulfonic acid6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester.

This ester was dissolved in DMF (420 mL), treated with sodium azide(33.40 g, 0.514 mol), and heated at 60° C. overnight. The mixture wascooled to room temperature and concentrated. The resultant slurry waspoured into brine (500 mL) and extracted with ether (4×500 mL). Thecombined organic extracts were washed with brine (2×100 mL), dried(Na₂SO₄), and concentrated. The crude material was filtered (eluantCH₂Cl₂) through a short plug of silica gel to provide 23.18 g (42% from2,3-cycloheptenopyridine) of9-azido-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine as a red oil. ¹H NMR(CDCl₃) δ 1.53-1.66 (m, 1H), 1.73-2.14 (m, 5H), 2.63-2.72 (m, 1H),2.99-3.09 (m, 1H), 4.93 (dd, 1H, J=7.8, 1.7 Hz), 7.13 (dd, 1H, J=7.9,4.8 Hz), 7.44 (d, 1H, J=5.7 Hz), 8.39 (dd, 1H, J=4.8, 1.9 Hz).

To a solution of the azide (23.18 g, 0.123 mol) in methanol (150 mL) wasadded Palladium, 10 wt. % on activated carbon (1.95 g) and the resultantmixture was hydrogenated at 40 psi on a Parr shaker. The mixture wasvacuum filtered through celite and the cake was washed with methanol.The solvent was removed from the filtrate under reduced pressure and theoil obtained was distilled (Kugelrohr, bp 105-140° C. @ 0.2 Torr) toprovide 17.56 g (88%) of6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine as a pale yellowoil. ¹H NMR (CDCl₃) δ 1.23-1.37 (m, 1H), 1.43-1.57 (m, 1H), 1.78-2.10(m, 6H) including 2.04 (s, 2H), 2.71-2.85 (m, 2H), 4.19 (dd, 1H, J=10.0,1.5), 7.05 (dd, 1H, J=7.4, 4.9 Hz), 7.36 (d, 1H, J=5.9 Hz), 8.38 (d, 1H,J=4.9 Hz).

To a stirred solution of6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine (0.235 g, 1.45mmol) from above and NaBH(OAc)₃ (0.461 g, 2.18 mmol) in anhydrous CH₂Cl₂(8 mL) was added dropwise4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (0.263 g, 1.21mmol) in anhydrous CH₂Cl₂ (4 mL). The resultant mixture was stirred atroom temperature for 3 hours, diluted with CH₂Cl₂ (25 mL), and quenchedwith saturated aqueous NaHCO₃ (15 mL). The two phases were stirredtogether for 1 hour and then separated. The organic phase was dried(Na₂SO₄), filtered, and concentrated under reduced pressure.Purification of the crude material by flash column chromatography onsilica gel (30:1 CH₂Cl₂/MeOH followed by 20:1 CH₂Cl₂/MeOH) provided 0.34g (65%) of the amine as a colourless oil.

To a stirred solution of2-[4-(6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-ylamino)-butyl]-isoindole-1,3-dionefrom above (0.34 g, 0.94 mmol) in CH₃CN (5 mL) was addedN,N-diisopropylethylamine (0.30 mL, 1.7 mmol), KI (7.8 mg, 0.047 mmol)and 1-(tert-butoxycarbonyl)-2-(chloromethyl)benzimidazole (0.302 g, 1.13mmol). The resultant mixture was stirred at 60° C. overnight, cooled,and concentrated under reduced pressure. The residue was partitionedbetween CH₂Cl₂ (25 mL) and saturated aqueous NaHCO₃ (15 mL). The aqueousphase was extracted with CH₂Cl₂ (2×10 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. Purification of the crude materialby flash column chromatography on silica gel (50:1 CH₂Cl₂/MeOH) affordedthe desired alkylated amine (0.33 g, 60%) as a white foam.

To a stirred solution of2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (0.33 g, 0.56 mmol) from above in EtOH (4 mL) wasadded anhydrous hydrazine (0.090 mL, 2.8 mmol) and the resultant mixturestirred at room temperature for 16 hours. The mixture was filtered andconcentrated under reduced pressure. Purification of the crude materialby radial chromatography on silica gel (TLC grade 2 mm plate, 50:1:1CH₂Cl₂/MeOH/NH₄OH followed by 40:1:1 CH₂Cl₂/MeOH/NH₄OH) afforded 0.13 g(62%) of the free base of the title compound as a white foam. ¹H NMR(CDCl₃) δ 1.30-1.85 (m, 7H), 1.90-2.00 (m, 2H), 2.10-2.24 (m, 1H),2.40-2.52 (m, 1H), 2.57-2.78 (m, 4H), 3.15-3.27 (m, 1H), 3.77-3.86 (m,1H), 4.00 (d, 1H, J=18 Hz), 4.15 (t, 1H, J=6 Hz), 7.16 (dd, 1H, J=2.7,7.5 Hz), 7.20-7.26 (m, 4H), 7.48 (dd, 1H, J=1.5, 7.5 Hz), 7.56-7.69 (m,2H), 8.48 (dd, 1H, J=1.5, 4.8 Hz); ¹³C NMR (CDCl₃) δ 25.04, 27.46,27.85, 28.85, 31.63, 34.58, 42.25, 48.21, 51.26, 67.12, 122.18, 122.76,138.74, 145.95, 163.11. ES-MS m/z 364 (M+H). Anal. Calcd. forC₂₂H₂₉N₅.0.3CH₂Cl₂: C, 68.86; H, 7.67; N, 18.00. Found: C, 68.99; H,7.84; N, 17.63.

Example 38

COMPOUND 38: Preparation of(1H-benzoimidazol-2-ylmethyl)-[3-(1H-imidazol-4-yl)-propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-aminePreparation of 3-(1H-imidazol-4-yl)-propionic acid

A suspension of urocanic acid (2.00 g, 14.5 mmol) in H₂O (40 mL) wasshaken at room temperature with a suspension of 10% Pd/C (200 mg, 0.19mmol) under hydrogen atmosphere (30 psi) for 2 h. The catalyst wasremoved by filtration, and the filtrate was concentrated in vacuo togive a colourless solid (1.95 g, 96%). ¹H NMR (D₂O) δ 2.52 (t, 2H, J=7.2Hz), 2.92 (t, 2H, J=7.2 Hz), 7.16 (s, 1H), 8.49 (s, 1H).

Preparation of 3-(1H-Imidazol-4-yl)-propionic acid methyl ester

A solution of 3-(1H-imidazol-4-yl)-propionic acid (1.95 g, 13.9 mmol)and H₂SO₄ (catalytic) in MeOH (30 mL) was heated at reflux for 15 h,then concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (40 mL)and washed with saturated NaHCO₃(aq) (30 mL). The aqueous phase wassaturated with sodium chloride and extracted with EtOAc (4×25 mL). Thecombined organic phases were dried (MgSO₄) and concentrated in vacuo togive a yellow oil (1.93 g, 90%). ¹H NMR (CDCl₃) δ 2.68 (t, 2H, J=7.2Hz), 2.93 (t, 2H, J=7.2 Hz), 3.69 (s, 3H), 6.81 (s, 1H), 7.55 (s, 1H).

Preparation of 4-(3-Hydroxy-propyl)-imidazole-1-carboxylic acidtert-butyl ester

To a solution of 3-(1H-imidazol-4-yl)-propionic acid methyl ester (1.92g, 12.5 mmol) in THF (25 mL) was added LiAlH₄ (1.0 M/THF, 12.5 mL, 12.5mmol) at 0° C., and the mixture was stirred at 0° C. for 15 minutes. Tothe mixture was added H₂O (0.50 mL) followed by 15% NaOH(aq) (0.50 mL)and H₂O (1.5 mL). The mixture was allowed to warm to room temperaturethen filtered and concentrated in vacuo to give a colourless oil (930mg).

To a solution of the crude alcohol from above (930 mg) in THF (25 mL)was added di-t-butyl dicarbonate (2.40 g, 11.0 mmol), and the solutionwas stirred at room temperature for 3 days. The solution wasconcentrated in vacuo, and the crude material was purified by columnchromatography on silica gel (200:5:1 CH₂Cl₂/MeOH/NH₄OH) to givecolourless crystals (1.04 g, 37%). ¹H NMR (CDCl₃) δ 1.61 (s, 9H), 1.89(m, 2H), 2.69 (t, 2H, J=6.9 Hz), 2.98 (t, 1H, J=5.7 Hz), 3.73 (dd, 2H,J=12, 5.7 Hz), 7.10 (s, 1H), 7.99 (s, 1H).

Preparation of 4-(3-Oxo-propyl)-imidazole-1-carboxylic acid tert-butylester

To a solution of 4-(3-hydroxy-propyl)-imidazole-1-carboxylic acidtert-butyl ester (95 mg, 0.42 mmol) in CH₂Cl₂ (4 mL) was addedDess-Martin periodinane (214 mg, 0.505 mmol) at room temperature. Afterstirring at room temperature for 1 h, the mixture was diluted with EtOAc(20 mL), washed with 1 N NaOH(aq) (2×10 mL) and brine (10 mL), thendried (MgSO₄) and concentrated in vacuo to give a colourless oil (86 mg,91%). ¹H NMR (CDCl₃) δ 1.61 (s, 9H), 2.86 (m, 4H), 7.11 (s, 1H), 7.99(s, 1H), 9.84 (s, 1H).

Using General Procedure B: To a stirred solution of2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylicacid tert-butyl ester (145 mg, 0.383 mmol) and4-(3-oxo-propyl)-imidazole-1-carboxylic acid tert-butyl ester (86 mg,0.38 mmol) in THF (4 mL) was added NaBH(OAc)₃ (244 mg, 1.15 mmol) andthe mixture was stirred at room temperature for 16 h. Purification ofthe crude material by column chromatography on silica gel (200:5:1CH₂Cl₂/MeOH/NH₄OH) afforded a colourless oil (39 mg, 17%). ¹H NMR(CDCl₃) δ 1.64 (m, 20H), 1.92 (m, 2H), 2.14 (m, 1H), 2.44 (m, 2H),2.60-2.92 (m, 5H), 4.26 (dd, 1H, J=9.5, 5.9 Hz), 4.52 (d, 1H, J=16 Hz),4.66 (d, 1H, J=16 Hz), 6.85 (d, 1H, J=0.9 Hz), 6.95 (dd, 1H, J=7.5, 4.8Hz), 7.27 (m, 3H), 7.69 (m, 1H), 7.80 (m, 1H), 7.88 (d, 1H, J=1.2 Hz),8.37 (dd, 1H, J=4.5, 1.2 Hz).

A solution of2-{[[3-(1-tert-butoxycarbonyl-1H-imidazol-4-yl)-propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (39 mg, 0.066 mmol) in 3:1 TFA/CH₂Cl₂ (4 mL) wasstirred at room temperature for 30 minutes then concentrated in vacuo.The residue was partitioned between CH₂Cl₂ (15 mL) and 1 N NaOH(aq) (10mL), and the aqueous phase was extracted with CH₂Cl₂ (15 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuoto afford COMPOUND 38 as a yellow foam (24 mg, 80%). ¹H NMR (CDCl₃) δ1.67 (m, 3H), 1.86 (m, 1H), 2.00 (m, 1H), 2.16 (m, 1H), 2.42-2.87 (m,6H), 4.01 (m, 3H), 6.51 (s, 1H), 7.15 (m, 3H), 7.42 (m, 2H), 7.53 (m,2H), 8.54 (d, 1H, J=3.6 Hz); ¹³C NMR (CDCl₃) δ 21.66, 23.85, 24.01,28.39, 29.50, 49.64, 50.78, 62.36, 115.22, 118.74, 122.23, 122.74,134.47, 135.25, 135.58, 138.03, 139.02, 146.88, 156.37, 157.69. ES-MSm/z 387 (M+H). Anal. Calcd. for C₂₃H₂₆N₆.0.4CH₂Cl₂.0.9CH₄O: C, 64.96; H,6.82; N, 18.70. Found: C, 65.13; H, 6.93; N, 18.91.

Example 39

COMPOUND 39: Preparation of(1H-benzoimidazol-2-ylmethyl)-(3-pyridin-2-yl-propyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt) Preparation of 3-pyridin-2-yl-propionaldehyde

To a stirred suspension of 2-pyridinepropanol (1.00 g, 7.29 mmol), NMO(1.281 g, 10.94 mmol) and 3 Å molecular sieves (3.645 g) in CH₂Cl₂ (37mL) was added TPAP (256 mg, 0.73 mmol). The resulting black mixture wasstirred at room temperature overnight. The mixture was concentrated andfiltered through a silica gel plug. Purification by columnchromatography on silica gel (EtOAc, 100%) afforded the desired aldehyde(111 mg, 11%) as a yellow syrup. 1H NMR (CDCl₃) δ 2.90-2.95 (m, 2H),3.11 (t, 2H, J=7.0 Hz), 7.09 (dd, 1H, J=7.0, 4.8 Hz), 7.17 (d, 1H, J=7.8Hz), 7.54-7.63 (m, 1H), 8.48 (d, 1H, J=4.2 Hz), 9.86 (s, 1H).

To a stirred solution of the aldehyde from above (67.6 mg, 0.50 mmol)and2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylicacid tert-butyl ester (200 mg, 0.50 mmol) in THF (5 mL) was addedNaBH(OAc)₃ and the resultant mixture was stirred at room temperature for3 days. The reaction mixture was concentrated under reduced pressure,diluted with CH₂Cl₂ (75 mL) and washed consecutively with H₂O (5 mL),saturated aqueous NaHCO₃ (7 mL), and saturated aqueous NaCl (7 mL). Theaqueous layers were extracted with CH₂Cl₂ (20 mL) and the combinedorganic extracts were dried (MgSO₄), filtered and concentrated underreduced pressure. Purification by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 100:1:1) afforded the desired compound (172 mg) asan orange syrup which was used in the next reaction without furtherpurification.

To a solution of the amine from above (172 mg, 0.35 mmol) in CH₂Cl₂ (2mL) was added TFA (2 mL) and the resultant mixture was stirred overnightat room temperature. The reaction mixture was concentrated under reducedpressure, the syrup was dissolved in a minimum amount of H₂O andbasified with 1N NaOH (pH 10). CHCl₃ (75 mL) was added, the phases wereseparated and the aqueous layer was extracted with CHCl₃ (2×75 mL). Thecombined organic extracts were dried (MgSO₄), filtered and concentratedunder reduced pressure. Purification of the crude yellow syrup by columnchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 100:1:1) followed byradial chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 100:1:1)afforded the desired compound (97 mg, 70%) as a yellow syrup.

Using General Procedure D: Conversion of the yellow syrup from above tothe hydrobromide salt afforded COMPOUND 39 as a white solid. ¹H NMR(D₂O) δ 1.82-2.06 (m, 4H), 2.14-2.19 (m, 1H), 2.35-2.38 (m, 1H),2.51-2.61 (m, 1H), 2.85-3.01 (m, 5H), 4.36 (d, 1H, J=16.8 Hz), 4.47-4.56(m, 2H), 7.56-7.61 (m, 2H), 7.72-7.79 (m, 4H), 7.85 (dd, 1H, J=7.8, 6.0Hz), 8.30-8.35 (m, 2H), 8.48-8.51 (m, 1H), 8.62 (d, 1H, J=4.8 Hz); ¹³CNMR (D₂O) δ 20.41, 20.58, 27.61, 27.65, 30.85, 47.99, 51.00, 60.39,114.31, 125.32, 126.00, 127.00, 127.36, 130.96, 139.44, 140.71, 141.08,147.26, 148.16, 151.05, 151.41, 156.22. ES-MS m/z 398.3 (M+H). Anal.Calcd. for C₂₅H₂₇N₅.3.2HBr.1.2H₂O: C, 44.28; H, 4.85; N, 10.33; Br,37.71. Found; C, 44.31; H, 5.06; N, 10.19; Br, 37.71.

Example 40

COMPOUND 40: Preparation ofN-{4-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-benzenesulfonamide

To a solution ofN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(56 mg, 0.16 mmol) and DIPEA (33 μL, 0.19 mmol) in CH₂Cl₂ (1.0 mL)cooled to 0° C. was added PhSO₂Cl (45 μL, 0.35 mmol). The resultantmixture was stirred overnight at room temperature. The mixture wasconcentrated under reduced pressure, diluted with CH₂Cl₂ (75 mL) andwashed consecutively with H₂O (5 mL), saturated aqueous NaHCO₃ (7 mL)and saturated aqueous NaCl (7 mL). The aqueous layers were extractedwith CH₂Cl₂ (20 mL) and the combined organic extracts were dried(MgSO₄), filtered and concentrated under reduced pressure. The resultantdisulfonamide (98 mg) was used without further purification in the nextreaction.

The disulfonamide from above (98 mg, 0.16 mmol) was stirred in asaturated HBr (g) in AcOH solution (1.5 mL) for 3 hours. The mixture wasconcentrated in vacuo and a suspension of the resultant yellow syrup andpowdered K₂CO₃ (excess) in MeOH was stirred at room temperature for 1hour. The mixture was concentrated under reduced pressure, diluted withCH₂Cl₂ and filtered through Celite. The cake was washed with CH₂Cl₂ andthe combined filtrate was concentrated under reduced pressure.Purification of the crude yellow foam by column chromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH, 100:1:1) followed by radial chromatography onsilica gel (CH₂Cl₂/MeOH/NH₄OH, 100:1:1) afforded COMPOUND 40 (50 mg, 64%over 2 steps). ¹H NMR (CDCl₃) δ 1.42-1.46 (m, 3H), 1.61-1.75 (m, 1H),1.81-1.99 (m, 1H), 2.00-2.09 (m, 1H), 2.14-2.21 (m, 1H), 2.46-2.55 (m,1H), 2.67-2.90 (m, 6H), 3.91 (d, 1H, J=16.2 Hz), 3.98-4.05 (m, 2H), 5.80(br s, 1H), 7.12-7.21 (m, 3H), 7.39-7.44 (m, 3H), 7.48-7.57 (m, 3H),7.75-7.79 (m, 2H), 8.53-8.55 (m, 1H); ¹³C NMR (CDCl₃) 21.21, 23.06,25.25, 27.47, 29.10, 42.81, 49.38, 50.21, 61.41, 121.73, 122.29, 126.92,128.97, 132.37, 134.72, 137.51, 140.22, 146.71, 155.65, 157.25. ES-MSm/z 490.3 (M+H). Anal. Calcd. for C₂₇H₃₁N₅O₂S.1.0H₂O: C, 63.88; H, 6.55;N, 13.80; S, 6.32. Found: C, 63.91; H, 6.32; N, 13.46; S, 6.33.

Example 41

COMPOUND 41: Preparation of(2S)-2-Amino-5-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-pentanoicacid (hydrobromide salt)

To a solution of (2S)-5-amino-2-(tert-butoxycarbonylamino)-pentanoicacid tert-butyl ester (free base) (0.905 g, 3.11 mmol) in CH₃OH (15 mL)was added 6,7-dihydro-5H-quinolin-8-one (0.504 g, 3.43 mmol) and theresultant solution was stirred at room temperature for 5 hours. PowderedNaBH₄ (0.379 g, 9.98 mmol) was added, and the mixture was stirred atroom temperature for 25 minutes then concentrated under reducedpressure. The residue was dissolved in CH₂Cl₂ (100 mL) and brine (20mL). The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (3×20 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated. Purification of the crude material by columnchromatography on silica gel (20:1 CH₂Cl₂—CH₃OH) provided 0.700 g (54%)of(2S)-2-tert-butoxycarbonylamino-5-(5,6,7,8-tetrahydroquinolin-8-ylamino)-pentanoicacid tert-butyl ester as a yellow oil.

Using the General Procedure for N-alkylation: A solution of(2S)-2-(tert-butoxycarbonylamino)-5-(5,6,7,8-tetrahydroquinolin-8-ylamino)-pentanoicacid tert-butyl ester (0.700 g, 1.67 mmol),1-(tert-butoxycarbonyl)-2-(chloromethyl)-benzimidazole (0.690 g, 2.59mmol) and N,N-diisopropylethylamine (0.60 mL, 3.44 mmol) in CH₃CN (16mL) was heated at 60° C. for 24 hours. Purification of the crudematerial by column chromatography on silica gel (50:1 CH₂Cl₂-MeOH)provided 0.830 g (77%) of2-{[(4-tert-butoxycarbonyl-4-tert-butoxycarbonylamino-butyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester as a tan foam.

General Procedure D: Conversion of2-{[(4-tert-butoxycarbonyl-4-tert-butoxycarbonylamino-butyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (139 mg) to the hydrobromide salt withsimultaneous removal of the BOC-protecting groups and hydrolysis of thetert-butyl ester, followed by re-precipitation of the intermediate solidfrom methanol/ether, gave COMPOUND 41 (116 mg, 81%) as a tan solid(mixture of 2 diastereomers). ¹H NMR (D₂O) δ 1.54-1.84 (m, 5H),1.96-2.06 (m, 1H), 2.15-2.2.19 (m, 1H), 2.34-2.38 (m, 1H), 2.53-2.60 (m,1H), 2.80-2.87 (m, 1H), 2.99-3.01 (m, 2H), 3.82 (t, 1H, J=6.3 Hz), 4.38(d, 1H, J=16.8 Hz), 4.50-4.55 (m, 2H), 7.57-7.62 (m, 2H), 7.76-7.88 (m,3H), 8.33 (br d, 1H, J=5.1 Hz), 8.62 (br d, 1H, J=6.0 Hz); ¹³C NMR (D₂O)δ 20.32, 20.40, 23.87, 24.12, 27.63, 27.93, 28.04, 48.16, 51.34, 51.51,53.41, 53.54, 60.48, 60.58, 114.24, 125.92, 126.92, 130.98, 139.36,140.60, 148.08, 151.18, 151.61, 173.06; ES-MS m/z 394 (M+H). Anal.Calcd. for C₂₂H₂₇N₅O₂.2.9HBr.2.1H₂O: C, 39.68; H, 5.16; N, 10.52; Br,34.79. Found: C, 39.81; H, 5.19; N, 10.14; Br, 34.70.

Example 42

COMPOUND 42: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N⁴-cyclopropyl-N¹-(56,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (HBr salt)

1,4-Butanediol (0.90 ml, 10.16 mmol) was added to a stirred suspensionof NaH (246 mg, 10.25 mmol) in THF (20 ml) at room temperature andstirred for 30 minutes. Acetyl chloride (0.70 mL, 9.84 mmol) was thenadded to the thick white slurry. Following 45 minutes of stirring, thesolution was diluted with diethyl ether (30 mL) and 10 w/v %K₂CO_(3 (aq)). The phases were separated and the organic phase washedwith 10% K₂CO₃ (1×15 mL) and brine (1×15 mL). The combined aqueous phasewas extracted with diethyl ether (1×30 mL). The organic phase was dried(MgSO₄) and concentrated to afford 933 mg crude product as a colourlessliquid. Purification by column chromatography (25 g silica, 2:1hexanes:ethyl acetate) afforded 686 mg of acetic acid 4-hydroxy-butylester (51%). ¹H NMR (CDCl₃) δ 1.58-1.77 (m, 4H), 2.05 (s, 3H), 3.68 (t,2H, J=6.1 Hz), 4.10 (t, 2H, J=6.4 Hz).

Tetrapropylammonium perruthenate (195 mg, 0.555 mmol) was added to asolution of the mono-protected diol from above (715 mg, 5.41 mmol), aswell as crushed and dried 3 Å molecular sieves (2.71 g, 5.42 mmol) andNMO (953 mg, 8.13 mmol), in CH₂Cl₂ (27 mL) and the mixture stirred for75 minutes. The suspension was filtered through a plug of silica withethyl acetate to give 0.48 g of acetic acid 4-oxo-butyl ester as acolourless oil (68%). ¹H NMR (CDCl₃) δ 1.98 (pent, 4H, J=6.6 Hz), 2.05(s, 3H), 2.55 (t, 2H, J=7.4 Hz), 4.10 (t, 2H, J=6.4 Hz), 9.80 (s, 1H).

Using general procedure B: Reaction of cyclopropylamine (0.51 mL, 7.36mmol) and the mono-protected aldehyde from above (480 mg, 3.69 mmol)with NaBH(OAc)₃ (1.573 g, 7.42 mmol) in CH₂Cl₂ (18 mL) for 19 hoursprovided a crude product. Purification of the crude material by columnchromatography on silica gel (20 g silica, 50:1→25:1 CH₂Cl₂:CH₃OH)provided 293 mg (46%) of acetic acid 4-cyclopropylamino-butyl ester. 1HNMR (CDCl₃) δ 0.29-0.45 (m, 4H), 1.49-1.71 (m, 4H), 2.04 (s, 3H),2.07-2.14 (m, 1H), 2.70 (t, 2H, J=6.9 Hz), 4.07 (t, 2H, J=6.7 Hz).

Di-tert-butyl-dicarbonate (399 mg, 1.83 mmol) was added to a solution ofthe amine from above (293 mg, 1.71 mmol) in THF (8.5 mL) at roomtemperature and the solution was stirred for 75 minutes, after whichtime the solution was concentrated under reduced pressure. The residuewas diluted with CH₂Cl₂ (30 mL) and brine (20 mL). The phases wereseparated and the organic phase was washed with brine (2×20 mL). Thecombined aqueous phases were extracted with CH₂Cl₂ (2×20 mL). Thecombined organic phase was dried (Na₂SO₄) and concentrated under reducedpressure to give 622 mg colourless liquid containing acetic acid4-(tert-butoxycarbonyl-cyclopropyl-amino)-butyl ester and excessdi-tert-butyl-dicarbonate.

Potassium carbonate (2.53 g, 18.3 mmol) was added to a solution of theester from above (622 mg, 1.71 mmol) in methanol (10 ml) at roomtemperature and the suspension was stirred for 80 minutes. The solutionwas then diluted with distilled water (20 mL). The mixture was extractedwith CHCl₃ (4×20 mL). The organic phase was dried (Na₂SO₄) andconcentrated to afford 399 mg (100% over two steps) crudecyclopropyl-(4-hydroxy-butyl)-carbamic acid tert-butyl ester as acolourless oil.

Tetrapropylammonium perruthenate (65 mg, 0.185 mmol) was added to asuspension of the alcohol from above (399 mg, 1.74 mmol), NMO (305 mg,2.60 mmol) and 3A molecular seives (861 mg, 1.72 mmol) in dry CH₂Cl₂(8.5 mL) at room temperature and the mixture was stirred for 1 hour. Thesuspension was then filtered through silica gel with ethyl acetate. Thefiltrate was concentrated under reduced pressure to give 545 mg crudeproduct. This crude material was purified by column chromatography (28 gsilica, 10:1→4 5:1 hexanes:ethyl acetate) to give 63 mg (16%) of purecyclopropyl-(4-oxo-butyl)-carbamic acid tert-butyl ester and 434 mgimpure material. ¹H NMR (CDCl₃) δ 0.56-0.62 (m, 2H), 0.71-0.78 (m, 2H),1.45 (s, 9H), 1.62 (s, 1H), 1.87 (pent, 2H, J=7.3 Hz), 2.45 (t, 2H,J=6.6 Hz), 3.24 (t, 2H, J=7.2 Hz), 9.79 (s, 1H).

Using general procedure B: To a stirred solution of the N-protectedaldehyde from above (63 mg, 0.277 mmol) and[1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(103 mg, 0.273 mmol) in CH₂Cl₂ (2.5 mL) was added NaBH(OAc)₃ (86 mg,0.406 mmol) and the mixture was stirred for 19 hours. Purification ofthe crude yellow oil (165 mg) by radial chromatography (2 mm plate,150:1:1 CH₂Cl₂:CH₃OH:NH₄OH) afforded 116 mg (72%)2-{[[4-(tert-butoxycarbonyl-cyclopropyl-amino)-butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester.

Using the General Procedure D: The double-protected tertiary amine fromabove (116 mg, 0.197 mmol) was converted to COMPOUND 42 as a white solid(99 mg, 70%). ¹H NMR (D₂O) δ 0.76-0.79 (m, 4H), 1.54 (br s, 4H),1.81-1.85 (m, 1H), 1.95-2.07 (m, 1H), 2.15-2.19 (m, 1H), 2.34-2.38 (m,1H), 2.55-2.61 (m, 2H), 2.79-2.84 (m, 1H), 3.01 (br s, 4), 4.38 (d, 1H,J=17.4 Hz), 4.50-4.56 (m, 2H), 7.57-7.59 (m, 2H), 7.77-7.79 (m, 2H),7.83 (t, 1H, J=6.6 Hz), 8.33 (d, 1H, J=7.8 Hz), 8.62 (d, 1H, J=5.4 Hz).¹³C NMR (D₂O) δ 3.35, 20.45, 23.69, 25.57, 27.67, 30.32, 48.12, 48.32,51.71, 60.70, 114.28, 125.95, 126.94, 130.97, 139.34, 140.62, 148.12,151.26, 151.79. ES-MS m/z 390 (M+H). Anal Calc. forC₂₄H₃₁N₅.3.4HBr.3.0H₂O: C, 40.11; H, 5.67; N, 9.74; Br, 37.80. Found: C,40.33; H, 5.57; N, 9.60; Br, 37.63.

Example 43

COMPOUND 43: Preparation of(cis-2-aminomethyl-cyclopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt) Preparation of(cis-2-hydroxymethyl-cyclopropyl)-methanol

To a 0° C. solution of dimethyl cis-1,2-cyclopropanedicarboxylate (3.03g, 19.1 mmol) in THF (25 mL) under nitrogen was slowly added LiA1H₄ (1.0M in hexane, 25 mL). The resulting mixture was stirred at roomtemperature for 1.5 hours, then was quenched by the careful addition ofH₂O (1 mL), 15% NaOH (1 mL) and H₂O (3 mL). The precipitate was removedby suction filtration, washing with EtOAc and the filtrate wasconcentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/MeOH, 19:1) gave the diol as acolourless liquid (1.79 g, 17.5 mmol, 92%). ¹H NMR (CDCl₃) δ 0.21 (dd,1H, J=10.5, 5.4 Hz), 0.80 (td, 1H, J=8.3, 5.1 Hz), 1.24-1.38 (m, 2H),3.16-3.29 (m, 4H), 4.02-4.14 (m, 2H).

Preparation of[cis-2-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopropyl]-methanol

To a 0° C. suspension of NaH (60% in mineral oil, 733 mg, 18.3 mmol) inTHF (25 mL) under nitrogen was added a solution of the diol (1.78 g,17.4 mmol) in THF (10 mL). The mixture was stirred for 10 minutes, thent-BDMSCI (2.73 g, 18.1 mmol) was added at once as a solid. The reactionwas stirred at room temperature for 25 minutes, then saturated aqueousNaHCO₃ (35 mL) was added, the layers were separated and the aqueoussolution was extracted with CH₂Cl₂ (25 mL×2). The combined organicsolution was dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification by flash column chromatography on silica(hexane/EtOAc, 4:1) gave the silane as a pale yellow liquid (3.12 g,14.4 mmol, 83%). ¹H NMR (CDCl₃) δ 0.09 (s, 3H), 0.11 (s, 3H), 0.19 (dd,1H, J=10.5, 4.5 Hz), 0.76 (td, 1H, J=7.5, 6.0 Hz), 0.91 (s, 9H),1.17-1.29 (m, 1H), 1.30-1.43 (m, 1H), 3.19-3.32 (m, 3H), 3.96 (td, 1H,J=11.5, 5.3 Hz), 4.14 (dd, 1H, J=11.7, 5.4 Hz).

Preparation oftert-butyl-(cis-2-chloromethyl-cyclopropylmethoxy)-dimethyl-silane

To a solution of the alcohol (3.11 g, 14.4 mmol) and NEt₃ (3.0 mL, 21.5mmol) in CH₂Cl₂ (45 mL) under nitrogen was added MsCl (1.65 mL, 21.3mmol). The reaction was heated at reflux for 17 hours. Once cooled toroom temperature, saturated aqueous NaHCO₃ (45 mL) was added, the layerswere separated and the aqueous solution was extracted with CH₂Cl₂ (25mL). The combined organic solution was dried (MgSO₄), filtered andconcentrated under reduced pressure. Purification by flash columnchromatography on silica (hexane/EtOAc, 9:1) gave the chloride as alight yellow liquid (1.52 g, 6.46 mmol, 45%). ¹H NMR (CDCl₃) δ 0.06 (s,3H), 0.07 (s, 3H), 0.40 (dd, 1H, J=10.5, 4.6 Hz), 0.84-0.93 (m, 10H),1.23-1.42 (m, 2H), 3.57-3.72 (m, 3H), 3.81 (dd, 1H, J=11.6, 5.7 Hz).

Preparation of N-(cis-2-hydroxymethyl-cyclopropylmethyl)-phthalimide

A mixture of the chloride (1.51 g, 6.43 mmol) and potassium phthalimide(1.31 g, 7.07 mmol) in DMF (25 mL) was heated to 80° C. for 3.5 hours.Once cooled to room temperature, H₂O (25 mL) was added and the mixturewas extracted with CH₂Cl₂ (25 mL×3). The combined organic solution wasdried (MgSO₄), filtered and concentrated under reduced pressure givingthe crude phthalimide as a yellow oil.

To a solution of this material in THF (15 mL) was added a 1M HClsolution (15 mL) and the reaction was stirred at room temperature for 30minutes. The THF was evaporated under reduced pressure and the aqueoussolution was extracted with CH₂Cl₂ (25 mL×3). The organic solution wasdried (Na₂SO₄), filtered and concentrated under reduced pressure.Purification by flash column chromatography on silica (EtOAc/hexane,1.5:1) gave the alcohol as a white solid (880 mg, 3.80 mmol, 59%). ¹HNMR (CDCl₃) δ 0.18 (dd, 1H, J=12.5, 5.0 Hz), 0.79 (td, 1H, J=8.8, 5.2Hz), 1.18-1.34 (m, 2H), 2.93 (br. s, 1H), 3.50-3.60 (m, 2H), 3.92-4.01(m, 2H), 7.71-7.75 (m, 2H), 7.83-7.87 (m, 2H).

Preparation of cis-[2-(phthalimidomethyl)-1-cyclopropyl]methylmethanesulfonate

To a 0° C. solution of the alcohol (443 mg, 1.92 mmol) and NEt₃ (0.40mL, 2.9 mmol) in CH₂Cl₂ (7 mL) under nitrogen was added a solution ofMsCl (0.22 mL, 2.8 mmol) in CH₂Cl₂ (0.8 mL). The reaction was stirred at0° C. for 15 minutes, then saturated aqueous NaHCO₃ (10 mL) was added.The layers were separated and the aqueous solution was extracted withCH₂Cl₂ (15 mL×2). The combined organic solution was dried (MgSO₄),filtered and concentrated under reduced pressure. Purification by flashcolumn chromatography on silica (EtOAc/hexane, 1:1) gave the mesylate asa white solid (513 mg, 1.66 mmol, 86%). ¹H NMR (CDCl₃) δ 0.52 (dd, 1H,J=11.4, 5.7 Hz), 1.89 (td, 1H, J=8.4, 5.4 Hz), 1.32-1.45 (m, 1H),1.53-1.66 (m, 1H), 3.01 (s, 3H), 3.71 (dd, 1H, J=14.4, 7.8 Hz), 3.79(dd, 1H, J=14.4, 7.8 Hz), 4.23 (dd, 1H, J=11.0, 8.9 Hz), 4.57 (dd, 1H,J=11.1, 6.9 Hz), 7.70-7.75 (m, 2H), 7.83-7.88 (m, 2H).

Preparation of(cis-2-aminomethyl-cyclopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

A solution of the mesylate (371 mg, 1.20 mmol),(1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(379 mg, 1.00 mmol), DIPEA (0.26 mL, 1.5 mmol) and KI (19 mg, 0.11 mmol)in CH₃CN (7 mL) was heated to 60° C. under nitrogen for 19 hours. Oncecooled, saturated aqueous NaHCO₃ (10 mL) was added and the mixture wasextracted with CH₂Cl₂ (25 mL×3). The combined organic solution was dried(MgSO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1)gave the tertiary amine (yellow foam) as an approximately 3:1 mixture ofdiastereomers (432 mg, 73%).

This material (420 mg, 0.71 mmol) and hydrazine monohydrate (0.35 mL,7.2 mmol) in EtOH (9 mL) was heated at reflux under nitrogen for 1 hour.Once cooled, the solvent was evaporated under reduced pressure. Theresidue was taken up into saturated aqueous NaHCO₃ (10 mL) and extractedwith CH₂Cl₂ (25 mL×3). The combined organic solution was dried (MgSO₄),filtered and concentrated under reduced pressure. Purification by flashcolumn chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 19:1:0. 1, followedby 9:1:0.05) gave the fully deprotected amine as a white foam (147 mg,0.41 mmol, 58%). ¹H NMR (CDCl₃) δ −0.15-0.02 (m, 1H), 0.49-0.59 (m, 1H),0.72-0.92 (m, 2H), 1.64-1.81 (m, 1H), 1.86-1.98 (m, 1H), 1.99-2.11 (m,2H), 2.15-2.32 (m, 2H), 2.47-2.61 (m, 1H), 2.66-2.90 (m, 3H), 2.96-3.13(m, 1H), 3.89 (2×d, 0.3H, J=15.1 Hz), 4.06 (s, 0.7 H), 4.13 (dd, 0.7 H,J=10.1, 5.9 Hz), 4.40 (2×d, 0.3H, J=6.2 Hz), 7.02-7.09 (m, 1H),7.15-7.20 (m, 2H), 7.37 (d, 1H, J=7.5 Hz), 7.52-7.62 (m, 2H), 8.51 (d,1H, J=3.3 Hz).

Preparation of COMPOUND 43

To a solution of the amine (75 mg, 0.21 mmol) in glacial HOAc (1.0 mL)was added a saturated solution of HBr in HOAc (0.5 mL). The solution wasstirred at room temperature for 25 minutes, then Et₂O (5 mL) was added.The precipitate was washed with Et₂O (1 mL×5) and dried at 90° C. underreduced pressure giving COMPOUND 43 as a yellow solid (131 mg, 0.19mmol, 91%). ¹H NMR (MeOH-d₄) δ 0.23-0.32 (m, 0.7H), 0.36-0.45 (m, 0.3H),0.51-0.69 (m, 1H), 1.01-1.20 (m, 1H), 1.33-1.57 (m, 1H), 1.87-2.04 (m,1H), 2.06-2.31 (m, 2H), 2.37-2.60 (m, 1H), 2.63-2.88 (m, 2H), 2.99-3.27(m, 4H), 4.52-4.83 (m, 3H), 7.57-7.67 (m, 2H), 7.86-8.02 (m, 3H),8.38-8.46 (m, 1H), 8.87-8.95 (m, 1H). ¹³C NMR (D₂O) δ 10.0 and 10.9,12.4 and 13.6, 15.5, 20.4 and 20.6, 20.7, 27.7, 39.8, 48.6, 51.7 and52.6, 61.3 and 62.0, 114.2, 125.9, 126.9, 130.9, 139.3 and 139.4, 140.5and 140.6, 148.1, 151.0 and 151.2, 151.9 and 152.6. ES-MS m/z 362 (M+H).Anal. Calcd. for C₂₂H₂₇N₅.3.2HBr.2.4H₂O.0.3C₄H₁₀O: C, 40.63; H, 5.58; N,10.21; Br, 37.28. Found: C, 40.61; H, 5.45; N, 10.10; Br, 37.19.

Example 44

COMPOUND 44: Preparation of(trans-2-aminomethyl-cyclopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydroquinlin-8-yl-amine(hydrochloride salt) Preparation of trans-1,2-cyclopropanedimethanol

To a solution of diethyl trans-1,2-cyclopropanedicarboxylate (14.9 g, 80mmol) in THF (50 mL), cooled to 0° C. under nitrogen, was added dropwisea 1.0 M solution of LAH in THF (107 mL, 107 mmol). The resultant mixturewas heated at reflux for 2 hours, then cooled to room temperature andstirred for 16 h. The crude mixture was cooled to 0° C. and carefullyquenched by the slow addition of deionized water (4 mL), followed by 15%NaOH solution (4 mL), and more deionized water (12 mL). The mixture wasstirred at room temperature for 20 min. The thick slurry was dilutedwith diethyl ether (100 mL), dried over MgSO₄, filtered through a glasssintered funnel, and concentrated in vacuo to afford the title compoundas a colorless oil (6.30 g, 78%). ¹H NMR (CDCl₃) δ 0.43 (t, 2H, J=6.8Hz), 0.96-1.07 (m, 2H), 3.05 (dd, 2H, J=11.4, 8.7 Hz), 3.13 (br. s, 2H),3.83 (dd, 2H, J=11.4, 4.7 Hz).

Preparation oftrans-1-hydroxymethyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopropane(McDougal, P. G., Rico J. G.; Oh Y.; Condon, B. D. J. Org. Chem. 1986,51, 3388-3390):

To a cooled (0° C. ) stirred solution oftrans-1,2-cyclopropanedimethanol (2.0 g, 20 mmol) in THF (40 mL) wasslowly added NaH (60% dispersion in oil, 0.80 g, 20 mmol). Stirring wascontinued at 0° C. for 10 min. tert-Butyldimethylchlorosilane (3.0 g, 20mmol) was added. The thick white slurry was allowed to warm to roomtemperature and stirring was continued for 10 min. The resultant mixturewas poured into diethyl ether (400 mL) and washed with 10% K₂CO₃ (100mL) then washed again with brine (100 mL). The separated organic layerwas dried over Na₂SO₄ and concentrated. The crude material was purifiedby flash column chromatography (5 cm id., 100 g silica gel, eluted with5:1 hexanes/ethyl acetate) to give the mono-protected desired product asa clear oil (2.8 g, 65%). ¹H NMR (CDCl₃) δ 0.05 (s, 6H), 0.41-0.53 (m,2H), 0.89 (s, 9H), 0.89-1.04 (m, 2H), 1.41 (t, 1H, J=5.8 Hz), 3.41-3.50(m, 3H), 3.60 (dd, 1H, J=11.2, 5.8 Hz).

Preparation of trans-N-{[2-(hydroxymethyl)cyclopropyl]methyl}phthalimide

To a stirred solution oftrans-1-hydroxymethyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopropane(4.7 g, 22 mmol) and triethylamine (9.2 mL, 65 mmol) in CH₂Cl₂ (75 mL)was added dropwise methanesulfonyl chloride (3.7 mL, 48 mmol). Themixture was heated at reflux for 16 h, then allowed to cool to roomtemperature. Deionized water (50 mL) was added to the red solution andthe layers were separated. The organic layer was washed with brine (50mL), dried over MgSO₄, and concentrated to a red oil. The crude materialwas purified by flash column chromatography (5 cm id., 140 g silica gel,eluted with 5% EtOAc/hexanes) to give the chloride as a yellow oil (4.0g, 78%).

The chloride from above (4.0 g, 17 mmol) and potassium phthalimide (4.8g, 26 mmol) were stirred in anhydrous DMF (115 mL) at 100° C., under anitrogen atmosphere, for 3 h. The mixture was concentrated to removeDMF. The resultant residue was diluted with CH₂Cl₂ (200 mL), washed withbrine (50 mL), dried over MgSO₄, and concentrated in vacuo. The crudematerial was purified by flash chromatography (5 cm id., 160 g silicagel, eluted with 10:1 hexanes/ethyl acetate) to provide the phthalimideas a pale yellow oil (5.4 g, 92%).

The phthalimide from above (5.3 g, 15 mmol) was stirred in a mixture ofTHF (40 mL) and 1N HCl (40 mL) for 1.5 h. The THF was removed in vacuoand the solution was extracted with CH₂Cl₂ (3×50 mL). The separatedorganic layers were combined, dried over MgSO₄, and concentrated. Thecrude material was purified by flash column chromatography (5 cm id.,120 g silica gel, 1:1 hexanes/ethyl acetate) to afford the pure titlecompound as a white solid (3.5 g, 97%). ¹H NMR (CDCl₃) δ 0.50 (ddd, 1H,J=8.4, 5.1, 5.1 Hz), 0.66 (ddd, 1H, J=8.4, 5.1, 5.1 Hz), 1.13-1.25 (m,2H), 1.50 (br. s, 1H), 3.33-3.43 (m, 1H), 3.45-3.53 (m, 1H), 3.60 (dd,2H, J=6.9, 5.1 Hz), 7.69-7.74 (m, 2H), 7.82-7.86 (m, 2H).

Preparation of2-[(trans-2-phthalimidomethyl-cyclopropylmethyl)-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl)-aminomethyl]-benzimidazole-1-carboxylicacid tert-butyl ester

To a 0° C. solution oftrans-N-{[2-(hydroxymethyl)cyclopropyl]methyl}phthalimide (3.4 g, 15mmol) and triethylamine (8.4 mL, 60 mmol) in CH₂Cl₂ (50 mL) was addeddropwise methanesulfonyl chloride (2.9 mL, 37 mmol). The mixture washeated at reflux for 18 h, cooled to room temperature and washed withdeionized water (100 mL), followed by saturated NaHCO₃ (100 mL), andfinally washed with brine (100 mL). The separated organic layer wasdried over MgSO₄ and concentrated to a tan solid. The crude solid waspurified by flash column chromatography (5 cm id., 100 g silica gel,eluted with 9:1 hexanes/ethyl acetate) to give the chloride as anoff-white solid (3.2 g, 85%).

Sodium iodide (12 g, 80 mmol) was added to a solution of the chloridefrom above (2.0 g, 8.0 mmol) in acetone (40 mL). The mixture was stirredvigorously at reflux for 68 h, then cooled to room temperature andconcentrated. The residue was partitioned between deionized water (100mL) and CH₂Cl₂ (100 mL). The separated organic layer was dried overMgSO₄ and concentrated to an orange solid (3.2 g). This material wasused without further purification.

A solution of the iodide from above (2.7 g, 8.0 mmol),(1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(2.9 g, 7.6 mmol) and DIPEA (2.1 mL, 12 mmol) in CH₃CN (40 mL) washeated at 60° C., under nitrogen, for 15.5 hours. Once cooled to roomtemperature, the mixture was concentrated, saturated aqueous NaHCO₃ (100mL) was added and the aqueous layer was extracted with CHCl₃ (3×100 mL).The combined organic portions were dried (MgSO₄), filtered andconcentrated under reduced pressure giving a brown foam. Purification byflash column chromatography on silica (5 cm id., 170 g silica gel,eluted with 2% MeOH/CH₂Cl₂) followed by a second column chromatographypurification of the product containing material (5 cm id., 150 g silicagel, eluted with 5% NH₄OH/EtOAc) gave a 1:1 mixture of two diastereomersof the title compound as a pale yellow foam (2.7 g, 59%). ¹H NMR (CDCl₃)δ 0.17-0.27 (m, 1H), 0.42-0.51 (m, 1H), 0.89-1.11 (m, 2H), 1.69 and 1.70(2×s, 9H), 1.79-2.02 (m, 3H), 2.08-2.20 (m, 1H), 2.52-2.83 (m, 4H), 3.16(dd, 0.5H, J=14.2, 7.7 Hz), 3.34 (dd, 0.5H, J=14.2, 7.7 Hz), 3.50-3.58(m, 1H), 4.24-4.34 (m, 1H), 4.40-4.52 (m, 1H), 4.62 (d, 1H, J=16.5 Hz),6.88-6.94 (m, 1H), 7.18-7.29 (m, 4H), 7.57-7.64 (m, 2H), 7.67-7.76 (m,2H), 7.78-7.83 (m, 1H), 8.28-8.33 (m, 1H).

Preparation of(trans-2-aminomethyl-cyclopropylmethyl)-(1H-benz-imidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydroquinlin-8-yl-amine

A solution of2-[(trans-2-phthalimidomethyl-cyclopropylmethyl)-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl)-aminomethyl]-benzimidazole-1-carboxylicacid tert-butyl ester (3.5 g, 5.9 mmol) and hydrazine hydrate (1.76 mL,35 mmol) in EtOH (27 mL) was stirred at room temperature under nitrogenfor 2 h. The white slurry was diluted with diethyl ether, filtered, andthe filtrate was concentrated. The crude material was purified by flashcolumn chromatography (5 cm id., 80 g silica gel, eluted with 2%NH₄OH/2%MeOH/CH₂Cl₂) to afford the pure title compound as a pale yellowfoamy solid (1.8 g, 83%). ¹H NMR (CDCl₃) δ 0.15-0.31 (m, 2H), 0.58-0.74(m, 2H), 1.59-1.76 (m, 1H), 1.79-1.92 (m, 1H), 1.96-2.07 (m, 1H),2.15-2.91 (m, 7H), 4.06-4.16 (m, 2H), 4.21 (2×d, 1H, J=14.6 Hz),7.10-7.22 (m, 3H), 7.41 (d, 1H), J=7.5 Hz), 7.54-7.62 (m, 2H), 8.57 (d,1H, J=4.5 Hz).

Preparation of(trans-2-aminomethyl-cyclopropylmethyl)-(1H-benz-imidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydroquinlin-8-yl-amine(hydrochloride salt) (COMPOUND 44)

A stirred solution of(trans-2-aminomethyl-cyclopropylmethyl)-(1H-benz-imidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydroquinlin-8-yl-amine(1.7 g, 4.8 mmol) in glacial acetic acid (10 mL) was treated with asaturated solution of HCl_((g)) in glacial acetic acid (10 mL). Theresultant solution was added dropwise to diethyl ether (300 mL) withvigorous stirring. Once the addition was complete, the white precipitatewas allowed to settle and the clear liquid was decanted. The solid waswashed repeatedly with ether (4×300 mL), decanting each time. The solidwas then collected on a sintered glass funnel, rinsed with diethyl ether(3×50 mL), and dried in a vacuum oven at 40° C. for 60 h to affordCOMPOUND 44 as a white solid (2.1 g, 88%, 1:1 mixture of diastereomers).¹H NMR (D₂O) δ 0.11-0.18 (m, 0.5H), 0.30-0.41 (m, 1H), 0.44-0.50 (m,0.5H), 0.69-0.87 (m, 2H), 1.71-1.86 (m, 1H), 1.91-2.52 (m, 5H), 2.70(ddd, 1H, J=27.0, 13.2, 6.0 Hz), 2.90-2.99 (m, 3H), 4.33-4.61 (m, 3H),7.51-7.55 (m, 2H), 7.72-7.83 (m, 3H), 8.26 (t, 1H, J=7.6 Hz), 8.59 (t,1H, J=7.6 Hz); ¹³C NMR (D₂O) δ 10.12, 11.19, 13.71, 15.45, 16.88, 17.04,20.42, 20.56, 20.63, 27.62, 43.20, 43.31, 48.93, 49.64, 55.43, 55.73,61.58, 61.89, 114.38, 125.71, 126.38, 126.43, 131.75, 132.04, 139.54,140.30, 147.54, 147.64, 151.27, 152.28. ES-MS m/z 362 (M+H). Anal.Calcd. for C₂₂H₂₇N₅.2.9HCl.1.7H₂O: C, 53.08; H, 6.74; N, 14.07; Cl,20.65. Found: C, 52.91; H, 6.90; N, 14.20; Cl, 20.90.

The enantiomeric purity of COMPOUND 44 was determined to be 100% bychiral HPLC using the following conditions: Instrument: Hewlett Packard1100 HPLC (VWD1); Column: ChiralCel OD, 0.46 cm×25 cm; Mobile Phases:A=90:10 hexanes/reagent alcohol with 0.1%DEA, B=hexanes; Isocratic: 50%A, 50%B; Total Run Time: 30 min; Flow Rate: 1.0 mL/min; Temperature: 40°C. ; Detector: UV @ 270 nm; Injection volume: 20 μL.

Retention time of the S enantiomer=13.0 min.

Retention time of the R enantiomer=16.7 min.

Example 45

COMPOUND 45: Preparation ofN′-(1H-benzimidazol-2-ylmethyl)-3-methyl-3-phenyl-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

Preparation of 2-methyl-2-phenyl-pent-4-enal (prepared as described byCiganek, E.; Read, J. M.: Calabrese, J. C. J. Org. Chem. 1995, 60,5795-5802)

A solution of 2-phenylpropionaldehyde (9.90 mL, 74.5 mmol), allylalcohol (20.4 mL, 300 mmol) and p-toluene sulfonic acid (0.8560 g, 4.5mmol) in benzene (37 mL) was heated to reflux for 19 hours and aDean-Stark trap was used to collect the water formed. The mixture wascooled to room temperature and saturated aqueous NaHCO₃ (5 mL) and H₂O(5 mL) were added. The phases were separated and the organic layer waswashed a second time with saturated aqueous NaHCO₃ (5 mL) and H₂O (5mL). The organic layer was dried (MgSO₄) and concentrated under reducedpressure. A solution of the resultant yellow residue in p-xylene (150mL) was heated to reflux for 24 hours. The solution was cooled to roomtemperature and concentrated under reduced pressure. The resultantaldehyde (13.0 g) was used in the next reaction without furtherpurification.

Preparation of acetic acid 2-methyl-2-phenyl-pent-4-enyl ester

To a solution of 2-methyl-2-phenyl-pent-4-enal (1.23 g, 7.02 mmol) inethanol (20 mL) was added sodium borohydride (0.80 g, 21.15 mmol) andthe resultant suspension was stirred at room temperature for 3 days. Themixture was concentrated under reduced pressure, diluted in saturatedNaHCO₃ (10 mL), and extracted with chloroform (5×25 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered, concentrated, and driedin vacuo to afford a yellow oil (1.04 g), which was used without furtherpurification in the next step.

To a solution of the crude alcohol from above (360 mg, 2.03 mmol),4-dimethylaminopyridine (24.4 mg, 0.20 mmol) and triethylamine (340 μL,2.44 mmol) in CH₂Cl₂ (10 mL) was added acetic anhydride (230 μL) and theresultant mixture was stirred at room temperature overnight. Then themixture was quenched with saturated NaHCO₃ (30 mL) and the phases wereseparated. The aqueous layer was washed with CH₂Cl₂ (2×20 mL). Then thecombined organic extracts were washed with saturated NaHCO₃ (2×30 mL),dried (MgSO₄), filtered, concentrated, and dried in vacuo to afford ayellow oil. Purification by column chromatography on silica gel(CH₃OH/CH₂Cl₂, 1:9) afforded the title compound (400 mg, 70% over 2steps). ¹H NMR (CDCl₃) δ 1.36 (s, 3H), 2.01 (s, 3H), 2.45 (qd, 2H,J=29.1, 16.2, 7.1 Hz), 4.19 (q, 2H, J=11.1, 7.8 Hz), 4.97-5.05 (m, 2H),5.48-5.54 (m, 1H), 7.21-7.44 (m, 5H).

Preparation of acetic acid 2-methyl-5-oxo-2-phenyl-pentyl ester

To a solution of the acetate from above (400 mg, 1.82 mmol) and4-methylmorpholine N-oxide (427 mg, 3.65 mmol) in CH₂Cl₂ (10 mL) wasadded osmium tetraoxide (2.5% in t-butanol) (680 μL, 0.06 mmol) and themixture was stirred at room temperature overnight. Then the mixture wasdiluted with ethyl acetate and filtered through a layer of celite. Thefiltrate was concentrated under reduced pressure and was dried in vacuoto afford an orange oil. Partial purification by column chromatographyon silica gel (CH₃OH/NH₄—OH/CH₂Cl₂, 4:1:95) followed by radialchromatography on silica gel (2 mm plate, CH₃OH/CH₂—Cl₂, 0:100 then2:98) afforded the diol (198 mg) as a yellow oil, which was used withoutfurther purification in the next step.

To a solution of the crude diol from above (198 mg, 0.82 mmol) in THF (5mL) and H₂O (1 mL) was added sodium periodate (351 mg, 1.64 mmol) andthe mixture was stirred for 2 hours at room temperature. The mixture wasdiluted with CH₂Cl₂ (15 mL) and washed with saturated NaCl (15 mL). Theaqueous layer was washed with CH₂Cl₂ (15 mL). Then the combined organicextracts were dried (MgSO₄), filtered, concentrated, and dried in vacuoto cleanly afford the product as a pale yellow oil (146 mg, 36% over 2steps). ¹H NMR (CDCl₃) δ 1.53 (s, 3H), 2.03 (s, 3H), 2.81 (ABqd, 2H,J=49.2, 15.9, 2.7 Hz), 3.75 (t, 1H, J=6.3 Hz), 4.23 (ABq, 2H, J=20.4,11.1 Hz), 7.24-7.34 (m, 4H), 7.38 (d, 1H, J=3.0 Hz), 9.54 (t, 1H, J=3.0Hz).

Preparation of4-[1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-2-methyl-2-phenyl-butan-1-ol

To a solution of the2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzimidazole-1-carboxylicacid tert-butyl ester (299 mg, 0.79 mmol) and the above aldehyde (146mg, 0.66 mmol) in CH₂Cl₂ (4 mL) was added sodium triacetoxyborohydride(251 mg, 1.18 mmol) and the mixture was stirred at room temperature for3 days. The mixture was diluted with CH₂Cl₂ (10 mL) and was extractedwith NaOH (1N, 2×10 mL) and brine (2×10 mL). The organic layer was dried(Na₂SO₄), filtered, concentrated, and dried in vacuo to afford a darkyellow oil. Partial purification by two attempts of radialchromatography on silica gel (2 mm plate, CH₃OH/NH₄OH/CH₂Cl₂, 0:1:99then 3:1:96), and (2 mm plate, NH₄OH/CH₂—Cl₂, 0:100 then 1:99) affordedthe compound as a yellow oil (198 mg), which was used without furtherpurification

To a solution of the crude amine from above (198 mg, 0.34 mmol) inmethanol (3.5 mL) was added potassium carbonate (84 mg, 0.61 mmol) andthe mixture was stirred at room temperature for 1 hour. Then the solventwas removed under reduced pressure and dissolved in CH₂Cl₂. The mixturewas filtered to remove the inorganic salt and the filtrate wasconcentrated and dried in vacuo to afford a yellow oil. Purification byradial chromatography on silica gel (1 mm plate, CH₃OH/NH₄OH/CH₂Cl₂,1:1:98 then 3:1:96) to afford the product as a pale yellow foam (85 mg,24% over 2 steps). ¹H NMR (CDCl₃) δ 1.20 and 1.26 (s, total 3H),1.65-1.68 (m, 2H), 1.93-2.01 (m, 3H), 2.13-2.16 (m, 1H), 2.53-2.74 (m,3H), 3.53-3.76 (m, 2H), 3.91-4.01 (m, 3H), 7.00-7.09 (m, 3H), 7.17-7.19(m, 3H), 7.26-7.29 (m, 2H), 7.41 (t, 2H, J=7.8 Hz), 7.64-7.67 (br m,1H), 8.43 and 8.47 (d, total 1H, J=3.5 Hz).

To a solution of the above alcohol (80 mg, 0.15 mmol) in CH₂Cl₂ (1.5 mL)was added Dess-Martin reagent (75 mg, 0.18 mmol) and the mixture wasstirred at room temperature for 20 minutes. Saturated NaHCO₃ (1 mL) andaqueous sodium dithionite (20%, 1 mL) was added to the mixture andstirred until the layers clarified. The mixture was diluted with CH₂Cl₂(5 mL) and the phases were separated. The aqueous layer was washed withCH₂Cl₂ (3×10 mL). Then the combined organic extracts were dried(Na₂SO₄), filtered, concentrated, and dried in vacuo to afford a yellowfoam (91 mg), which was used without further purification.

Preparation ofN′-(1H-benzimidazol-2-ylmethyl)-3-methyl-3-phenyl-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-14-diamine

To a solution of the crude aldehyde from above (90 mg, 0.17 mmol) inmethanol (1.5 mL) was added hydroxyamine hydrochloride salt (23 mg, 0.33mmol) and the mixture was stirred at room temperature for 40 minutes.The mixture was concentrated under reduced pressure and the residue wasdissolved in CH₂Cl₂ (5 mL). The mixture was basified to pH9 withsaturated NaHCO₃ and the phases were separated. The aqueous layer wasextracted with CH₂Cl.₂(2×10 mL). Then the combined organic extracts weredried (Na₂SO₄), filtered, concentrated, and dried in vacuo to afford apale yellow foam (72 mg), which was used without further purification.

To a solution of the crude oxime from above (285 mg, 0.63 mmol) inmethanol (20 mL) was added a slurry of Raney-nickel in water(approximately 30 mg). The mixture was purged with ammonium gas and thenhydrogenated overnight at 35 psi. Then the mixture was filtered througha layer of celite and the filtrate was concentrated and dried in vacuoto afford a yellow oil. Purification by three attempts at radialchromatography on silica gel (2 mm plate, CH₃OH/NH₄OH/CH₂Cl₂, 0:1:99then 1:1:98), (2 mm plate, CH₃OH/NH₄OH/CH₂, 1:1:98 then 3:1:96), (1 mmplate, CH₃OH/NH₄OH/CH₂Cl₂, 1:1:98 then 2:1:97) to afford the minor spotCOMPOUND 45 as a yellow foam (16 mg, 4% over 3 steps). ¹H NMR (CDCl₃) δ1.21 and 1.25 (s, total 3H), 1.62-2.05 (m, 6H), 2.25-2.80 (m, 7H), 3.48(q, 1H, J=6.9 Hz), 3.89-4.15 (m, 3H), 7.00-7.26 (m, 8H), 7.36-7.38 (m,1H), 7.58 (br s, 2H), 8.58 (br m, 1H). ¹³C NMR (CDCl₂) δ 21.70, 23.07,23.71, 29.36, 30.09, 38.19, 38.57, 46.76, 49.87, 49.96, 62.02, 62.20,122.10, 122.44, 126.34, 126.49, 126.56, 128.68, 128.97, 134.87, 137.63,147.11, 147.20. ES-MS m/z 440 [M+H]+. Anal. Calcd. forC₂₈H₃₃N₅.0.2CH₂Cl₂.0.6C₄H₁₀O: C, 73.35; H, 7.93; N, 1398. Found: C,72.97; H, 7.87; N, 13.78.

Example 46

COMPOUND 46(R), COMPOUND 46(S): Preparation of(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-phenyl-1-aminobut-4-yl)-amine(hydrobromide salt)

NOTE: Synthesis of COMPOUND 46(R) is listed below, proceeding from(R)-(N-t-butoxycarbonyl)-2-phenylglycinol. The synthesis of COMPOUND46(S) proceeds identically from the (S)-isomer.

A solution of DMSO (2.13 mL, 30 mmol) in dichloromethane (100 mL) waschilled under nitrogen to −60° C. To this stirred solution, oxalylchloride (15 mL of a 2.0 M solution in dichloromethane, 30 mmol) wasadded over five minutes. The mixture was stirred at −60° C. for tenminutes, then a solution of (R)-(N-t-butoxycarbonyl)-2-phenylglycinol(5.3 g, 20 mmol) in dichloromethane (40 mL) was added over ten minutes.The mixture was stirred at −60° C. for 20 minutes, then triethylamine(8.35 mL, 60 mmol) was added. The mixture was stirred gradually warmingto room temperature, over 60 minutes. A saturated aqueous solution ofammonium chloride (75 mL) was then added. The aqueous and organic layerswere separated, and the aqueous layer was washed twice withdichloromethane. The combined organic fractions were then dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to afford(R)-(N-t-butoxycarbonyl)-2-phenylglycinal as an unstable yellow oil,which was used immediately without further purification in the nextreaction (assuming 100% conversion). ¹H NMR (CDCl₃) δ 1.43 (s, 9H), 5.31(m, 1H), 5.75 (br s, 1H (NH)), 7.30-7.41 (m, 5H), 9.55 (s, 1H).

The aldehyde was dissolved in benzene (150 mL), and methyl(triphenylphoshporanylidene) acetate (6.96 g, 20 mmol) was added. Themixture was then stirred at room temperature overnight. The suspensionwas then concentrated in vacuo and loaded directly onto a silica gelcolumn (1:1 hexanes:ethyl acetate). The product (E)-methyl4-[(t-butoxycarbonyl)-amino]-4-phenylbut-2-enoate was collected as acolourless oil in a yield of 3.17 g (52%). s, 9H), 3.71 (s, 3H), 4.95(m, 1H), 5.56 (br s, 1H (Nh)), 5.96 (dd, 1H, J=15.2, 2.9 Hz), 7.05 (dd,1H, J=15.2, 4.1 Hz), 7.27-7.49 (m, 5H).

To a solution of methyl4-[(t-butoxycarbonyl)-amino]-4-phenylbut-2-enoate (3.17 g) in methanol(100 mL) was added palladium on carbon (250 mg (10% by wt. Pd)). Themixture was then placed under 50 psig hydrogen gas, and was shaken on aParr hydrogenator for 2 hours. The mixture was then filtered throughcelite, concentrated in vacuo and purified by silica gel flashchromatography (3:1 hexanes:ethyl acetate) to afford methyl4-[(t-butoxycarbonyl)-amino]-4-phenylbutanoate as a pale yellow oil in ayield of 2.61 g (82%). ¹H NMR (CDCl₃) δ 1.45 (s, 9H), 2.07 (m, 2H), 2.36(m, 2H), 3.69 (s, 3H), 4.59 (m, 1H), 5.15 (br s, 1H (NH)), 7.21-7.34 (m,5H).

To a 0° C. solution of methyl4-[(t-butoxycarbonyl)-amino]-4-phenylbutanoate (293 mg, 1.0 mmol) indichloromethane (25 mL) was added Dibal-H (3 mL of a 1.0 M solution indichloromethane, 3.0 mmol). The mixture was then stirred at 0° C. for 2hours before being quenched with a saturated aqueous sodium potassiumtartrate solution (10 mL). The biphasic mixture was then rapidly stirredfor approximately 45 minutes, until the aqueous and organic layersclarified. The aqueous and organic layers were then separated and theaqueous layer was extracted twice with dichloromethane. The combinedorganic fractions were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to afford a pale yellow residue, which waspurified by silica gel flash chromatography (1:1 hexanes:ethyl acetate)to afford 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanol as a colourlessoil in a yield of 138 mg (52%). ¹H NMR (CDCl₃) δ 1.43 (s, 9H), 1.45 (m,2H), 1.56 (m 2H), 2.71 (br s, 1H (OH)), 3.54 (t, 2H, J=6.9 Hz), 4.56 (m,1H), 5.22 (br s, 1H (NH)), 7.16-7.26 (m, 5H).

To a 0° C. solution of 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanol (133mg, 0.5 mmol) in dichloromethane (8 mL) was added triethylamine (0.140mL, 1.0 mmol), followed by methanesulfonylchloride (0.057 mL, 0.75mmol). The solution was then stirred at 0° C. for 15 minutes beforebeing quenched with an aqueous ammonium chloride solution (2 mL). Theaqueous and organic layers were then separated, the aqueous layerextracted twice with dichloromethane, and the combined organic fractionswere dried over anhydrous sodium sulfate, filtered and concentrated invacuo to afford 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanol mesylate asa yellow oil, which was used immediately in the next reaction withoutfurther purification. ¹H NMR (CDCl₃) δ 1.43 (s, 9H), 1.67-2.00 (m, 4H),2.95 (s, 3H), 4.18 (t, 2H, J=7.1 Hz), 4.20 (m, 1H), 4.92 (br s, 1H(NH)), 7.21-7.33 (m, 5H).

To a solution of the mesylate (0.5 mmol, assumed 100% conversion fromthe previous step) in dimethylformamide (5 mL) was added sodium azide(130 mg, 2 mmol). The mixture was then heated to 70° C. for 2 hoursunder nitrogen. After cooling, the reaction was diluted with 40 mL ethylacetate, and extracted repeatedly with distilled water. The organicfraction was then dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gel flashchromatography (1:1 hexanes:ethyl acetate) to afford4-[(t-butoxycarbonyl)-amino]-4-phenylbutyl azide in a yield of 100 mg(69% from alcohol). ¹H NMR (CDCl₃) δ 1.38 (s, 9H), 1.47-1.61 (m, 2H),1.78 (m, 2H), 3.25 (t, 2H, J=6.8 Hz), 4.58 (m, 1H), 4.97 (m, 1H (NH)),7.20-7.33 (m, 5H).

To a solution of the azide (100 mg, 0.34 mmol) in methanol (20 mL) wasadded Lindlar's catalyst (5% Pd on CaCO₃, poisoned with lead (15 mg)).The mixture was then placed under 1 atmosphere H₂ and was stirredovernight. The mixture was then filtered through celite, concentrated invacuo and purified by silica gel flash chromatography (15% Methanol, 1%NH₄OH in dichloromethane) to afford4-amino-1-phenyl-1-(t-butoxycarbonyl)-amine in a yield of 65 mg (72%).¹H NMR (CDCl₃) δ 1.40 (s, 9H), 1.77 (m, 2H), 2.29 (m, 2H), 2.70 (t, 2H,J=7.8 Hz), 4.58 (m, 1H), 5.11 (m, 1H (NR)), 7.20-7.33 (m, 5H).

To a solution of 5,6,7,8-tetrahydroquinolin-8-one (40 mg, 0.271 mmol)and 4-amino-1-phenyl-1-(t-butoxycarbonyl)-amine (65 mg, 0.246 mmol) indichloromethane (8 mL) was added sodium triacetoxyborohydride (115 mg,0.542 mmol). The reaction was then stirred overnight at roomtemperature. A saturated sodium carbonate solution (5 mL) was added, andthe aqueous and organic layers were then separated. The aqueous layerwas extracted twice with dichloromethane and the combined organicfractions were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gel flashchromatography to yield and4-[(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-1-phenyl-1-(t-butoxycarbonyl)-aminein a yield of 65 mg (61%). ¹H NMR (CDCl₃) δ 1.40 (s, 9H), 1.61-1.85 (m,6H), 1.94 (m, 1H), 2.04 (m, 1H), 2.74 (m, 4H), 3.78 (m, 1H), 4.91 (m,1H), 5.35 (m, 1H (NH)), 7.07 (dd, 1H, J=8.1, 4.9 Hz), 7.24-7.28 (m, 5H),7.36 (d, 1H, J=8.1 Hz), 8.36 (d, 1H, J=4.9 Hz).—fix 1H

To a solution of (N-t-butoxycarbonyl)-2-chloromethylbenzimidazole (53mg, 0.20 mmol),4-[(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-1-phenyl-1-(t-butoxycarbonyl)-amine(65 mg, 0.165 mmol) and diisopropylethylamine (0.043 mL, 0.25 mmol) inacetonitrile (5 mL) were stirred at 70° C. for 16 hours. After cooling,the mixture was diluted with dichloromethane (20 mL) and washed with asaturated sodium bicarbonate solution (5 mL). The aqueous and organiclayers were then separated, and the aqueous layer was extracted twicewith dichloromethane. The combined organic fractions were then driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified by silica gel flash chromatography to affordN-[(t-butoxycarbonyl)-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-phenyl-1-aminobut-4-yl)-(t-butoxycarbonyl)-amineas a pale foam in a yield of 73 mg (71%). 1H NMR (CDCl₃) δ 1.40 (s, 9H),1.63 (s, 9H), 1.71-2.11 (m, 8H), 2.58-2.79 (m, 4H), 4.16 (dd, 1H,J=10.9, 8.1 Hz), 4.43 (m, 3H), 5.05 (m, 1H (NH)), 6.96 (m, 1H),7.15-7.31 (m, 8H), 7.75 (m, 1H), 7.83 (m, 1H), 8.30 (m, 1H).

Using General Procedure D: Conversion of the foam from above (72 mg,0.117 mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 46(R) (58 mg, 70%)as a beige solid. ¹H NMR (D₂O) δ 0.83 (m, 1H), 1.84 (m, 5H), 2.06-2.20(m, 2H), 2.30-2.55 (m, 2H), 2.90 (m, 2H), 4.05 (m, 1H), 4.22 (d, 1H,J=15.8 Hz), 4.45 (m, 1H), 4.48 (d, 1H, J=15.8 Hz), 7.07-7.18 (m, 5H),7.62 (m, 2H), 7.73 (m, 2H), 7.87 (dd, 1H, J=13.2, 5.7 Hz), 8.28 and 8.31(d, 1H total, J=5.7 Hz (each doublet from a diastereomer)), 8.54 (d, 1H,J=5.4 Hz); ¹³C NMR (D₂O) δ 20.59, 25.10, 25.23, 27.59, 30.46, 30.56,49.59, 55.04, 55.50, 61.15, 61.98, 114.29, 125.92, 126.94, 127.28,127.39, 129.47, 129.61, 129.84, 129.92, 130.82, 139.07, 139.23, 140.41,148.13, 151.72. ES-MS m/z 426 (M+H). Anal. Calcd. forC₂₇H₃₁N₅.3.0HBr.2.6H₂O: C, 45.35; H, 5.52; N, 9.79; Br, 33.52. Found: C,45.72; H, 5.34; N, 9.43; Br, 33.34.

COMPOUND 46(S) was prepared using the same procedure described abovefrom 73 mg (0.117 mmol) ofN-[(t-butoxycarbonyl)-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-phenyl-1-aminobut-4-yl)-(t-butoxycarbonyl)-amineto afford 49 mg (58%) of the hydrobromide salt as a white solid. ¹H, ¹³Cand MS data identical to that for COMPOUND 46(R). Anal. Calcd. forC₂₇H₃₁N₅.3.0HBr.2.7H₂O: C, 45.23; H, 5.54; N, 9.77; Br, 33.43. Found: C,45.52; H, 5.49; N, 9.39; Br, 33.45.

Example 47

COMPOUND 47: Preparation of(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-aminobutan-3-ol-4-yl)-amine

To a solution of 3-buten-1-ol (10 g, 138 mmol) in dichloromethane (150mL) was added acetic anhydride (13 mL, 138 mmol) and4-dimethylaminopyridine (244 mg, 2 mmol). The mixture was then stirredat room temperature for 8 hours. The reaction mixture was then pouredinto a saturated aqueous sodium bicarbonate solution (100 mL). Afterseparation of the aqueous and organic layers, the aqueous layer wasextracted twice with 100 mL portions of dichloromethane. The combinedorganic fractions were then dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to afford 3-buten-I-yl acetate as acolourless oil in a yield of 12.9 g (82%). ¹H NMR (CDCl₃) δ 2.04 (s,3H), 2.38 (m, 2H), 4.11 (t, 3H, J=7.1 Hz), 5.04 (d, 1H, J=9.1 Hz), 5.08(d, 1H, J=15.3 Hz), 5.77 (m, 1H).

To a solution of 3-buten-1-yl acetate (5.7 g, 50 mmol) indichloromethane (200 mL) was added m-chloroperoxybenzoic acid (12.9 g,75 mmol). The reaction was then stirred at room temperature for 3 hours.The reaction mixture was then filtered through celite and concentratedin vacuo. The residue was purified by silica gel flash chromatography(4:1 hexanes:ethyl acetate) to yield 3,4-epoxybutan-1-yl acetate as acolourless oil in a yield of 3.8 g (58%). ¹H NMR (CDCl₃) δ 1.78-1.88 (m,2H), 2.03 (s, 3H), 2.47 (m, 1H), 2.75 (m, 1H), 2.99 (m, 1H), 4.18 (t,1H, J=6.6 Hz).

To a solution of 3,4-epoxybytan-1-yl acetate (3.9 g, 29 mmol) in DMF (50mL) was added potassium phthalimide (6.47 g, 35 mmol). The stirredmixture was then heated to 90° C. for 16 hours. After cooling, themixture was diluted with ethyl acetate (200 mL) and extracted repeatedlywith water. The organic fraction was then dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bysilica gel flash chromatography (1:1 hexanes:ethyl acetate) to affordN-(3-hydroxybutan-4-yl-1-acetate)-phthalimide as a pale yellow oil in ayield of 1.65g (20%). ¹H NMR (CDCl₃) δ 1.69-1.88 (m, 2H), 2.04 (s, 3H),2.90 (m, 1H (Oh)), 3.79 (d, 2H, J=5.7 Hz), 4.03 (m, 1H), 4.21-4.31 (m,2H), 7.70 (m, 2H), 7.83 (m, 2H). MS m/z 300 (M+Na).

To a solution of afford N-(3-hydroxybutan-4-yl-1-acetate)-phthalimide(554 mg, 2.0 mmol) in acetonitrile (15 mL) was added imidazole (150 mg,2.2 mmol) and t-butyldimethylsilyl chloride (310 mg, 2.05 mmol). Themixture was then stirred overnight at room temperature. Dichloromethane(50 mL) was then added to the reaction, and the mixture was extractedwith a saturated ammonium chloride solution. The organic layer was thendried over anhydrous sodium sulfate, filtered and concentrated to leavea yellow oily residue which was purified by silica gel flashchromatography (3:1 hexanes:ethyl acetate) to affordN-(3-t-butyldimethylsiloxybutan-4-yl-1-acetate)-phthalimide in a yieldof 570 mg (73%). ¹H NMR (CDCl₃) δ −0.04 (s, 3H), −0.01 (s, 3H), 0.84 (s,9H), 1.78 (m, 2H), 3.68 (dd, 1H, J=8.1, 6.5 Hz), 3.73 (dd, 1H, J=8.1,6.2 Hz), 4.15 (m, 3H), 7.71 (m, 2H), 7.85 (m, 2H).

To a stirred −78° C. solution of affordN-(3-t-butyldimethylsiloxybutan-4-yl-1-acetate)-phthalimide (670 mg,1.71 mmol) in THF (20 mL) was added DIBAL-H (5.1 mL of a 1.0M solutionin hexanes, 5.1 mmol). The reaction was stirred at −78° C. for 45minutes, then a saturated solution of ammonium chloride (5 mL) wasadded. The mixture was allowed to warm to room temperature, then ethylacetate (20 mL) and 1N HCl (2 mL) were added. The mixture was thenshaken in a separatory funnel to speed the clarification of the layers,then the organic and aqueous layers were separated. The aqueous layerwas extracted twice with ethyl acetate, then the combined organicfractions were separated and the aqueous layer was extracted twice withethyl acetate. The combined organic fractions were then dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by silica gel flash chromatography (1:1hexanes:ethyl acetate) to affordN-(3-t-butyldimethylsiloxybutan-1-ol-4-yl)-phthalimide as a colourlessoil in a yield of 465 mg (78%). ¹H NMR (CDCl₃) δ −0.02 (s, 3H), 0.09 (s,3H), 0.86 (s, 9H), 1.71-1.82 (m, 2H), 2.11 (m, 1H (OH)), 3.76 (m, 4H),4.28 (m, 1H), 7.73 (m, 2H), 7.85 (m, 2H).

To a solution of N-(3-t-butyldimethylsiloxybutan-1-ol-4-yl)-phthalimide(160 mg, 0.4 mmol) in dichloromethane (10 mL) was added Dess-MartinPeriodinane (212 mg, 0.5 mmol). The mixture was then stirred at roomtemperature for 30 minutes. A 5% solution of sodium thiosulfate (10 mL)and a saturated sodium bicarbonate solution (10 mL) was added along withanother 20 mL of dichloromethane. The mixture was then stirred rapidlyfor 20 minutes, and the aqueous and organic layers were separated. Theaqueous layer was extracted twice with dichloromethane, and the combinedorganic fractions were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to affordN-(3-t-butyldimethylsiloxybutan-1-al-4-yl)-phthalimide as a yellow oil,which was used immediately in the next reaction without furtherpurification. ¹H NMR (CDCl₃) δ −0.02 (s, 3H), 0.05 (s, 3H), 0.81 (s,9H), 2.61 (m, 2H), 3.74 (m, 2H), 4.51 (m, 1H), 7.71 (m, 2H), 7.85 (m,2H), 9.81 (m, 1H).

To a solution of N-(3-t-butyldimethylsiloxybutan-1-al-4-yl)-phthalimide(0.4 mmol) in dichloromethane (15 mL) was added(5,6,7,8-tetrahydroquinolin-8-yl)-[(N-t-butoxycarbonyl)-benzimidazol-2-yl)methyl]-amine(151 mg, 0.4 mmol). The mixture was stirred at room temperature for 30minutes, then sodium triacetoxyborohydride (170 mg, 0.8 mmol) was added,and the reaction was allowed to stir for 16 hours. A saturated sodiumbicarbonate solution (10 mL) was added, and the aqueous and organiclayers were separated. The aqueous layer was then extracted twice withdichloromethane, and the combined organic fractions were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was then purified by silica gel flash chromatography (3%methanol in dichloromethane) to afford[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-3-(t-butyldimethylsiloxy)-4-yl)-amineas a pale yellow foam in a yield of 224 mg (79%). ¹H NMR (CDCl₃) δ −0.25(s, 3H), −0.23 (s, 3H), 0.69 (s, 9H), 1.44-1.63 (m, 4H), 1.68 (s, 9H),2.00 (m, 2H), 2.16 (m, 1H), 2.65-2.74 (m, 3H), 3.48-3.62 (m, 2H), 3.94(m, 1H), 4.23 (m, 1H), 4.44 (d, 1H, J=15.3 Hz), 4.72 (m, 1H, J=15.3 Hz),6.95 (m, 1H), 7.20 (m, 3H), 7.67 (m, 3H), 7.77 (m, 3H), 8.44 (m, 1H).

To a solution of[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-3-(t-butyldimethylsiloxy)-4-yl)-amine(170 mg, 0.24 mmol) in THF (8 mL) was added 1N HCl (2 mL). The mixturewas then heated to 50° C. for 2 hours. After cooling, dichloromethane(50 mL) was added, and the mixture was shaken with a saturated sodiumbicarbonate solution (20 mL). After separation of the aqueous andorganic layers, the aqueous layer was extracted twice withdichloromethane. The combined organic fractions were then dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to afford afoamy residue, which was purified by silica gel flash chromatography (5%methanol in dichloromethane) to afford(1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-3-ol-4-yl)-amineas a white foam in a yield of 73 mg (49%). ¹H NMR (CDCl₃) δ 1.50-1.59(m, 2H), 1.70-2.07 (m, 5H), 2.21 (m, 1H), 2.75-3.00 (m, 4H), 3.78-3.94(m, 2H), 4.00-4.22 (m, 2H), 7.04 (m, 1H), 7.16 (m, 2H), 7.24 (d, 1H,J=5.8 Hz), 7.68 (br s, 1H (NH)), 7.71 (m, 3H), 7.81 (m, 3H), 8.21 and8.42 (d, total of 1H, J=4.9, 5.1 Hz respectively).

To a solution of(1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-3-ol-4-yl)-amine(73 mg, 0.147 mmol) in denatured ethanol (5 mL) was added hydrazinehydrate (0.07 mL, 1.5 mmol). The mixture was then heated to reflux for60 minutes. After cooling, the reaction was concentrated in vacuo, takenup in dichloromethane (20 mL) and washed with an aqueous sodiumcarbonate solution (5 mL). The aqueous layer was then extracted twicewith dichloromethane, and the combined organic fractions were dried overanhydrous sodium sulfate, filtered and concentrated to afford a foamyresidue which was purified by silica gel flash chromatography (10%methanol, 0.5% ammonium hydroxide in dichloromethane) to afford(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-aminobutan-3-ol-4-yl)-amine(COMPOUND 47—diastereomeric mixture) as a white foam in a yield of 22 mg(41%). ¹H NMR (CDCl₃) δ 1.35 (m, 1H), 1.70-1.82 (m, 2H), 2.06 (m, 1),2.26 (m, 1H), 2.54-2.99 (m, 5H), 3.57 and 3.84 (m, total of 1H), 3.94(d, 1H, J=15.3 Hz), 4.01 (m, 1H), 4.13 (s, 1H), 4.13 (d, 1H, J=15.3 Hz),7.14-7.21 (m, 3H), 7.42 (d, 1H, J=7.5 Hz), 7.57 (m, 2H), 8.46 and 8.56(d, total of 1H, J=3.6, 3.6 Hz respectively); ¹³C NMR (CDCl₃) δ 21.57,22.25, 29.33, 31.52, 32.30, 46.46, 47.69, 48.69, 49.91, 62.15, 62.67,70.11, 74.23, 122.33, 122.67, 122.99, 135.61, 138.21, 146.93, 147.29,141.15, 154.89. ES-MS m/z 366 (M+H). Anal. Calcd. forC₂₁H₂₇N₅O.0.4CH₂Cl₂: C, 64.35; H, 7.01; N, 17.53. Found: C, 64.16; H,7.20; N, 17.22.

Example 48

COMPOUND 48: Preparation of(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-3-fluoro-butan-4-yl)-amine

To a 0° C. solution of(1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-3-ol-4-yl)-amine(81 mg, 0.163 mmol (preparation described above)) in dichloromethane (5mL) in a polyethylene test tube under a nitrogen atmosphere was addeddiethylaminosulfur trifluoride (0.065 mL, 0.5 mmol). The mixture wasstirred, gradually warming to room temperature for 2 hours. The mixturewas then poured into a saturated sodium bicarbonate solution (10 mL).The aqueous and organic layers were then separated, and the aqueouslayer was extracted twice with dichloromethane. The combined organicfractions were then dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gel flashchromatography (5% methanol in dichloromethane) to afford(1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-3-fluoro-butan-4-yl)-amineas a white foam in a yield of 55 mg (67%). ¹H NMR (CDCl₃) δ 1.69 (m,2H), 1.86-2.04 (m, 4H), 2.75-2.88 (m, 4H), 3.99 (m, 1H), 4.02-4.20 (m,4H), 5.01 and 5.08 (m, total of 1H), 7.13 (m, 4H), 7.26 (m, 1H),7.59-7.73 (m, 4H), 7.89 (m, 1H), 8.78 (m, 1H).

To a solution of(1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-3-fluoro-butan-4-yl)-amine(55 mg, 0.110 mmol) in denatured ethanol (5 mL) was added hydrazinehydrate (0.07 mL, 1.5 mmol). The mixture was then heated to reflux for60 minutes. After cooling, the reaction was concentrated in vacuo, takenup in dichloromethane (20 mL) and washed with an aqueous sodiumcarbonate solution (5 mL). The aqueous layer was then extracted twicewith dichloromethane, and the combined organic fractions were dried overanhydrous sodium sulfate, filtered and concentrated to afford a foamyresidue which was purified by silica gel flash chromatography (10%methanol, 0.5% ammonium hydroxide in dichloromethane) to afford(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-3-fluorobutan-4-yl)-amine(COMPOUND 48—diastereomeric mixture) as a white foam in a yield of 16 mg(40%). ¹H NMR (CDCl₃) δ 1.73 (m, 2H), 1.91-2.04 (m, 2H), 2.23 (m, 1H),2.61-2.86 (m, 6H), 4.00 (d, 1H, J=16.5 Hz), 4.05 (s, 1H), 4.07 (m, 1H),4.15 (m, 1H), 4.17 (d, 1H, J=16.5 Hz), 4.47 and 4.53 (m, total of 1H),7.14-7.22 (m, 4), 7.42 (d, 1H, J=8.1 Hz), 7.57 (m, 1H), 7.58 (br s, 1H(NH), 8.58 (d, 1H, J=4.5 Hz); ¹³C NMR (CDCl₃) δ 21.73 and 23.83 (d,total of 1C, J_(C-F)=23 Hz), 29.30, 29.54, 30.73, 39.09, 45.92 and 46.60(total of 1C), 47.35, 50.10 and 62.23 (d, total of 1C, J_(C-F)=27 Hz),92.65 and 95.11 (d, total of 1H, J_(C-F)=167 Hz), 115.38, 122.08,122.73, 129.19, 131.29, 135.07, 137.82, 137.98, 146.99, 147.11, 156.49,157.65. ES-MS m/z 368 (M+H). Anal. Calcd. forC₂₁H₂₆N₅F.0.1CH₂Cl₂.0.2C₆H₁₂: C, 68.19; H, 7.34; N, 17.83. Found: C,67.82; H, 7.14; N, 17.66.

Example 49

COMPOUND 49: Preparation of[3-(1-amino-cyclopropyl)-propyl]-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

Preparation of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acidethyl ester (Wentland, M. P.; Perni R. B.; Dorff, P. H.; Rake, J. B. J.Med. Chem. 1988, 31, 1694-1697.):

To a suspension of 1-aminocyclopropanecarboxylic acid (998 mg, 9.87mmol) in EtOH (25 mL), cooled to 0° C., was added SOCl₂ (2.0 mL, 27mmol) dropwise over 10 minutes. The resulting solution was heated atreflux under nitrogen for 2 hours, then was evaporated under reducedpressure, giving the ester as a light brown oil.

This material was dissolved into EtOAc (25 mL) and a solution of KHCO₃(1.51 g, 15.1 mmol) in H₂O (9 mL) was added dropwise. The resultingsolution was cooled to 0° C. and a solution of Boc₂O (2.97 g, 13.6 mmol)in EtOAc (10 mL) was added. The reaction was stirred at room temperaturefor 16 hours, the layers were separated and the aqueous solution wasextracted with EtOAc (25 mL). The combined organic solution was dried(MgSO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography on silica (EtOAc/hexane, 1:3) gave theprotected amine as light brown solid (1.27 g, 5.54 mmol, 56%). ¹H NMR(CDCl₃) δ 1.08-1.18 (m, 2H), 1.23 (t, 3H, J=7.2 Hz), 1.44 (s, 9H),1.46-1.53 (m, 2H), 4.14 (q, 2H, J=7.2 Hz), 5.13 (br. s, 1H).

Preparation of (1-hydroxymethyl-cyclopropyl)-carbamic acid tert-butylester

To a solution of the ester (1.18 g, 5.15 mL) in THF (10 mL) undernitrogen was added a solution of LiBH₄ (200 mg, 9.2 mmol) in THF (10 mL)dropwise over 10 minutes. The reaction was stirred at room temperaturefor 17.5 hours, then was cooled to 0° C. A solution of 50% HOAc wasadded dropwise until the evolution of gas had ceased (approx. 8 mL). Theresulting white suspension was diluted with H₂O (15 mL) and wasextracted with Et₂O (30 mL). The organic solution was washed with 15%aqueous NaHCO₃ (15 mL) and brine (15 mL), then dried (Na₂SO₄), filteredand concentrated under reduced pressure. Purification by flash columnchromatography on silica (EtOAc/hexane, 1:1) gave the alcohol as a whitesolid (592 mg, 3.16 mmol, 61%).² ¹H NMR (CDCl₃) δ 0.81 (s, 4H), 1.43 (s,9H), 3.52 (br. s, 1H), 3.58 (s, 2H), 5.12 (br. s, 1H).

Preparation of (1-formyl-cyclopropyl)-carbamic acid tert-butyl ester

To a solution of the alcohol (389 mg, 2.08 mmol) in CH₂Cl₂ (11 mL),cooled to 0° C., was added crushed, dried 3 Å molecular sieves (1.05 g),NMO (382 mg, 3.26 mmol) and TPAP (76 mg, 0.22 mmol). The black mixturewas stirred at 0° C. for 30 minutes and at room temperature for afurther 30 minutes. The mixture was diluted with EtOAc (20 mL) andflushed through a short silica column, rinsing with EtOAc. The productcontaining material was concentrated under reduced pressure giving thealdehyde as a white solid (345 mg, 1.86 mmol, 90%). ¹H NMR (CDCl₃) δ1.27-1.37 (m, 2H), 1.40-1.52 (m, 2H), 1.46 (s, 9H), 5.22 (bs. s, 1H),9.16 (s, 1H).

Preparation of (E)-3-(1-tert-butoxycarbonylamino-cyclopropyl)-acrylicacid ethyl ester

Triethyl phosphonoacetate (0.62 mL, 3.13 mmol) was added dropwise to asuspension of 60% NaH in mineral oil (120 mg, 3.00 mmol) in THF (5 mL).The resulting solution was stirred at room temperature for 10 minutes,then cooled to 0° C. for the dropwise addition of a solution of thealdehyde (463 mg, 2.50 mmol) in THF (5 mL). The reaction was stirred at0° C. for 15 minutes, then heated to reflux for 1 hour. Once cooled toroom temperature, saturated aqueous NH₄Cl (10 mL) was added, the layerswere separated and the aqueous solution was extracted with CH₂Cl₂ (10mL×2). The organic solution was dried (MgSO₄), filtered and concentratedunder reduced pressure. Purification by flash column chromatography onsilica (EtOAc/hexane, 1:1) gave the unsaturated ester as a pale yellowsolid (539 mg, 2.11 mmol, 84%). ¹H NMR (CDCl₃) δ 1.11-1.18 (m, 2H),1.24-1.29 (m, 5H), 1.44 (s, 9H), 4.17 (q, 2H, J=7.1 Hz), 5.02 (br. s,1H), 5.84 (d, 1H, J=15.3 Hz), 6.47 (d, 1H, J=15.6 Hz).

Preparation of 3-(1-tert-butoxycarbonylamino-cyclopropyl)-propionic acidethyl ester

A solution of the unsaturated ester (495 mg, 1.94 mmol) in EtOAc (10 mL)was hydrogenated (H₂ balloon) over 10% Pd/C (25 mg, 0.023 mmol) at roomtemperature for 3 hours. The mixture was suction filtered throughCelite, washing with EtOAc and evaporation of the filtrate under reducedpressure gave the saturated ester as a colourless oil (500 mg, 1.94mmol, 100%). ¹H NMR (CDCl₃) δ 0.61-0.65 (m, 1H), 0.73-0.78 (m, 1H), 0.91(t, 2H, J=7.4 Hz), 1.25 (td, 3H, J=7.1, 1.4 Hz), 1.43 (s, 9H), 1.78-1.90(m, 2H), 2.36 (t, 1H, J=7.7 Hz), 2.44 (t, 1H, J=7.5 Hz), 4.12 (q, 2H,J=7.1 Hz).

Preparation of [1-(3-hydroxy-propyl)-cyclopropyl]-carbamic acidtert-butyl ester

LiBH₄ (70 mg, 3.2 mmol) was added to a solution of the ester (500 mg,1.94 mmol) in THF (8 mL). The reaction was stirred at room temperatureunder nitrogen for 18 hours, then was quenched by the dropwise additionof 50% aqueous HOAc until the evolution of gas had ceased (approx. 2mL). The suspension was diluted with H₂O (10 mL) and extracted with Et₂O(15 mL). The organic solution was washed with saturated aqueous NaHCO₃(10 mL) and brine (10 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure. Purification by flash column chromatography onsilica (hexane/EtOAc, 2:1; increased to 1:1) gave the alcohol as acolourless oil (164 mg, 0.77 mmol, 40%). ¹H NMR (CDCl₃) δ 0.55-0.62 (m,2H), 0.69-0.75 (m, 2H), 1.40 (s, 9H), 1.52-1.72 (m, 4H), 2.10 (br. s,1H), 3.64 (t, 2H, J=6.3 Hz), 4.96 (br. s, 1H).

Preparation of{1-[3-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-propyl]-cyclopropyl]-carbamicacid tert-butyl ester

To a solution of the alcohol (160 mg, 0.74 mmol) in CH₂Cl₂ (4 mL),cooled to 0° C., was added crushed, dried 3 Å molecular sieves (374 mg),NMO (125 mg, 1.07 mmol) and TPAP (26 mg, 0.07 mmol). The reaction wasstirred at 0° C. for 25 minutes, then at room temperature for a further15 minutes. The reaction was diluted with EtOAc (8 mL) and the mixturewas flushed through a short silica column, eluting with EtOAc. Removalof the solvent under reduced pressure gave the aldehyde as a pale yellowoil (123 mg, 78%).

A solution of this material (120 mg, 0.56 mmol) and8-amino-5,6,7,8-tetrahydroquinoline (90 mg, 0.61 mmol) in MeOH (1.5 mL)was stirred at room temperature under nitrogen for 17 hours. NaBH₄ (35mg, 0.93 mmol) was added and the reaction was stirred for a further 15minutes. The solvent was evaporated under reduced pressure, the residuewas taken up into CH₂Cl₂ (20 mL) and was washed with saturated aqueousNaHCO₃ (5 mL) and brine (5 mL). The organic solution was dried (MgSO₄),filtered and concentrated under reduced pressure. Purification by flashcolumn chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1) gave thesecondary amine as an orange oil (51 mg, 0.15 mmol, 26%). ¹H NMR (CDCl₃)δ 0.57-0.63 (m, 2H), 0.69-0.76 (m, 2H), 1.42 (s, 9H), 1.56-1.80 (m, 5H),1.80-2.06 (m, 3H), 2.09-2.20 (m, 1H), 2.68-2.87 (m, 4H), 3.77 (t, 1H,J=6.3 Hz), 5.16 (br. s, 1H), 7.06 (dd, 1H, J=7.7, 4.7 Hz), 7.37 (d, 1H,J=7.5 Hz), 8.38 (d, 1H, J=4.2 Hz).

Preparation of2-{[[3-(1-tert-butoxycarbonylamino-cyclopropyl)-propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester

A solution of the secondary amine (51 mg, 0.147 mmol), tert-butyl2-chloro-methylbenzimidazole-1-carboxylate (47 mg, 0.18 mmol), DIPEA(0.04 mL, 0.2 mmol) and KI (5 mg, 0.03 mmol) in CH₃CN (0.8 mL) wasstirred at 60° C. under nitrogen for 18 hours. Once cooled to roomtemperature, saturated aqueous NaHCO₃ (5 mL) was added and the mixturewas extracted with CH₂Cl₂ (10 mL×3). The combined organic solution wasdried (MgSO₄), filtered and concentrated under reduced pressure.Purification by flash column chromatography on silica(CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1) gave the tertiary amine as a pale orangefoam (60 mg, 0.104 mmol, 71%). ¹H NMR (CDCl₃) δ 0.30-0.46 (m, 2H),0.48-0.63 (m, 2H), 1.29-1.50 (m, 11H), 1.60-1.76 (m, 12H), 1.79-1.90 (m,1H), 1.95-2.05 (m, 1H), 2.08-2.19 (m, 1H), 2.59-2.70 (m, 2H), 2.72-2.87(m, 2H), 4.26 (dd, 1H, J=9.5, 6.5 Hz), 4.50 (d, 1H, J=15.6 Hz), 4.63 (d,1H, J=15.0 Hz), 5.10 (br. s, 1H), 6.98 (dd, 1H, J=7.7, 4.7 Hz),7.26-7.32 (m, 3H), 7.72 (dd, 1H, J=6.2, 3.2 Hz), 7.83 (dd, 1H, J=6.0,3.0 Hz), 8.37 (d, 1H, J=3.0 Hz).

Preparation of COMPOUND 49

To a solution of the tertiary amine (57.6 mg, 0.100 mmol) in glacialHOAc (1.0 mL) was added a saturated solution of HBr in HOAc (0.5 mL).The reaction was stirred at room temperature for one hour and Et₂O (5mL) was added. The resulting sticky solid was washed with Et₂O (1 mL×2),then crushed with a spatula while under Et₂O (˜2 mL). The resultingprecipitate was washed with Et₂O (1 mL×2), then dried under reducedpressure affording COMPOUND 49 as an orange powder (65.7 mg, 0.091 mmol,91%). ¹H NMR (D₂O) δ 0.63-0.68 (m, 2H), 0.81-0.86 (m, 2H), 1.46-1.67 (m,4H), 1.76-1.90 (m, 1H), 1.93-2.06 (m, 1H), 2.12-2.22 (m, 1H), 2.31-2.41(m, 1H), 2.48-2.58 (m, 1H), 2.77-2.87 (m, 1H), 2.96-3.02 (m, 2H), 4.39(d, 1H, J=16.8 Hz), 4.47-4.56 (m, 2H), 7.59 (dd, 2H, J=6.2, 3.2 Hz),7.79 (dd, 2H, J=6.2, 3.2 Hz), 7.85 (dd, 1H, J=7.8, 6.0 Hz), 8.33 (d, 1H,J=7.8 Hz), 8.62 (d, 1H, J=5.4 Hz). ¹³C NMR (D₂O) 69.6, 20.4, 24.3, 27.6,31.8, 34.3, 48.0, 51.8, 60.5, 114.3, 125.9, 126.9, 131.0, 139.3, 140.6,148.1, 151.2, 151.7. ES-MS m/z 376 (M+H). Anal. Calcd. forC₂₃H₂₉N₅.3.1HBr.1.5C₂H₄O₂.0.2H₂O: C, 43.37; H, 5.39; N, 9.73; Br, 34.40.Found: C, 43.26; H, 5.67; N, 9.64; Br, 34.68.

Example 50

COMPOUND 50:(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(5-amino-pent-1-yl)-amine(Hydrobromide salt)

To a stirred solution of[1-(2-(trimethylsilyl)ethoxymethyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(188 mg, 0.455 mmol) and diisopropylethyl amine (0.26 ml<1.49 mmol) inCH₃CN was added 5-bromovaleronitrile (0.12 mL, 1.03 mmol). The mixturewas heated at 80° C. for 47 hours, after which time the reaction wascooled to room temperature. After removal of volatiles under reducedpressure, the residue was dissolved in CH₂Cl₂ (20 mL). The solution waswashed with brine (3×15 mL). The aqueous phase was extracted with CH₂Cl₂(1×15 mL). The combined organic phases were dried (Na₂SO₄), filtered andconcentrated under reduced pressure to give a crude orange oil (306 mg).Purification of this oil by column chromatography (1.75 cm OD, 14 gsilica, 40:1 CH₂Cl₂:CH₃OH) afforded the purified tertiary amine (110 mg,50%).

The amine from above (110 mg) was dissolved in ammonia saturated CH₃OH(12 mL) and treated with Raney-Nickel (410 mg). The mixture was shakenon a Parr hydrogenator at 50 psi H₂ for 20 hours, after which time themixture was filtered through celite and concentrated to give a crudeyellow-orange oil (124 mg).

The amine from above (124 mg) was dissolved in 4N HCl (2 mL) and heatedto 50° C. for 6 hours. The mixture was then cooled to room temperatureand basified with 10N NaOH (final pH>13). This aqueous phase wasextracted with CH₂Cl₂ (4×10 mL). The organic phase was then dried(Na₂SO₄), filtered and concentrated to give a crude brown foam (83 mg).Purification of this foam by radial chromatography on silica gel (40:1:1CH₂Cl₂:CH₃OH:NH₄OH) afforded the pure freebase (38 mg, 46% over twosteps).

Using the General Procedure D: Conversion of the freebase from above (38mg) to the hydrobromide salt gave COMPOUND 50 as a white solid (53 mg,76%). ¹H NMR (D₂O) δ 1.14-1.28 (m, 2H), 1.39-1.57 (m, 4H), 1.77-1.90 (m,1H), 1.96-2.10 (m, 1H), 2.13-2.23 (m, 1H), 2.31-241 (m, 1H), 2.46-2.57(m, 1H), 2.73-2.90 (m, 3H), 2.96-3.03 (m, 2H), 4.38 (d, 1H, J=16.7 Hz),4.47-4.57 (m, 2H), 7.60 (dd, 2H, J=6.3, 3.3 Hz), 7.80 (dd, 2H, J=6.2,3.1 Hz), 7.86 (dd, 1H, J=7.9, 6.0 Hz), 8.31 (d, 1H, J=7.0 Hz), 8.62 (d,1H, J=4.7 Hz). ¹³C NMR (D₂O) δ 20.40, 23.88, 26.92, 27.63, 27.87, 39.68,48.51, 52.09, 60.86, 114.26 (2 carbons), 125.85, 126.83 (2 carbons),131.17, 139.29, 140.47, 147.92 (2 carbons), 151.48, 152.00. ES-MS m/z364 (M+H) Anal Calc. for C₂₂H₂₉N₅.3.1HBr.2.6H₂O: C, 39.97; H, 5.69; N,10.59; Br, 37.46. Found: C, 39.96; H, 5.64; N, 10.62; Br, 37.36.

Example 51

COMPOUND 51:(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(6-amino-hex-1-yl)-amine(Hydrobromide salt) Preparation ofN-(tert-butoxycarbonyl)-6-amino-1-hexanal

Di-tert-butyl-dicarbonate (1.155 g, 5.29 mmol) was added to a solutionof 6-amino-1-hexanol (541 mg, 4.62 mmol) and diisopropylethyl amine(0.25 mL) in THF (10 mL). The mixture was stirred at ambient temperaturefor 18 hours, after which time the volatile components were removedunder reduced pressure. The residue was dissolved in CH₂Cl₂ (30 mL) andwashed with brine (3×20 mL). The organic phase was dried (Na₂SO₄),filtered and removed on a rotovap to leave a crude yellow oil (1.090g).

Some of the above-obtained oil (220 mg, 1.01 mmol) was dissolved inCH₂Cl₂ (5 mL) and treated with Dess-Martin periodinane (455 mg, 1.07mmol). After 2 hours, the reaction was diluted with diethyl ether (20mL) and treated with 20% w/v Na₂S₂O_(3 (aq)). The phases were separatedafter 10 minutes, and the aqueous phase was extraced with ether (3×10mL). The combined organic phase was washed with 20% w/v Na₂S₂O₃ (1×12mL), saturated aqueous NaHCO₃ (1×12 mL) and brine (1×12 mL). The organicphase was dried (MgSO₄), filtered and removed under reduced pressure togive a crude colourless oil (172 mg). This oil was purified by columnchromatography (1.75 cm OD, 14 g silica, 4:1 hexanes:ethyl acetate) togive 31 mg of desired intermediate (14%). ¹H NMR (CDCl₃) d 1.29-1.50(m,. 13H), 1.63 (pentet, 2H, J=7.4 Hz), 2.42 (td, 2H, J=7.2, 1.6 Hz),3.06-3.12 (m, 2H), 4.57 (br s, 1H), 9.74 (s, 1H).

Using the General Procedure B: To a stirred solution of[1-(2-(trimethylsilyl)ethoxymethyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(62 mg, 0.150 mmol) and N-(tert-butoxycarbonyl)-6-amino-1-hexanal (31mg, 0.144 mmol) in CH₂Cl₂ (2.5 mL) was added NaBH(OAc)₃ (66 mg, 0.311mmol) and the mixture stirred for 24 hours to afford a crude yellow oil(91 mg).

This oil (91 mg) was dissolved in 4N HCl (2 mL) and heated to 50° C.After 4 hours the reaction was allowed to cool. The reaction wasbasified with 10N NaOH (final pH>13) and the aqueous phase was extractedwith CH₂Cl₂ (8×7 mL). The organic phase was dried (Na₂SO₄), filtered andremoved on a rotovap to give 52 mg crude yellow oil freebase. This oilwas purified by radial chromatography on silica gel (40:1:1CH₂Cl₂:CH₃OH:NH₄OH) to give 36 mg yellow film (66% yield over twosteps).

Using the General Procedure D: conversion of the freebase from above (36mg) to the hydrobromide salt gave COMPOUND 51 as a white solid (53 mg,84%).

¹H NMR (D₂O) δ 1.13-1.23 (m, 4H), 1.31-1.56 (m, 4H), 1.75-1.90 (m, 1H),1.96-2.10 (m, 1H), 2.13-2.23 (m, 1H), 2.31-241 (m, 1H), 2.44-2.55 (m,1H), 2.71-2.81 (m, 1H), 2.85 (t, 2H, J=7.8 Hz), 2.97-3.04 (m, 2H), 4.38(d, 1H, J=17.0 Hz), 4.48-4.59 (m, 2H), 7.61 (dd, 2H, J=6.1, 3.1 Hz),7.80 (dd, 2H, J=6.1, 3.0 Hz), 7.86 (dd, 1H, J=7.7, 5.9 Hz), 8.34 (d, 1H,J=8.3 Hz), 8.62 (d, 1H, J=5.7 Hz). ¹³C NMR (D₂O) δ 20.39, 20.45, 25.81,26.41, 27.07, 27.64, 28.14, 39.74, 48.67, 52.22, 60.95, 114.24 (2carbons), 125.86, 126.88 (2 carbons), 131.01, 139.21, 140.49, 147.99,151.55, 152.12. ES-MS m/z 378 (M+H) Anal Calc. for C₂₃H₃₁N₅.3.1HBr.1.9H₂O: C, 41.69; H, 5.77; N, 10.57; Br, 37.38. Found: C, 41.77;H, 5.60; N, 10.60; Br, 37.36.

Example 52

COMPOUND 52: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-cis-1,4-diamine(hydrobromide salt) Preparation of4-[N-(tert-butyloxycarbonyl)]amino-cyclohexanone

A solution of trans-4-aminocyclohexanol hydrochloride (2.67 g, 1.14 mol)in 1 N NaOH (40 mL) was washed with CHCl₃ (40 mL), CH₂Cl₂ (2×30 mL) andEtOAc (4×30 mL). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated in vacuo to afford the desired free base (0.43g) as a white solid. To a suspension of trans-4-aminocyclohexanol (0.43g, 4.09 mmol) in THF (20 mL) was added di-tert-butyl dicarbonate (0.89g, 4.09 mmol) and the mixture stirred at room temperature for 2 hours.The mixture was concentrated under reduced pressure and the resultantcrude product was used without further purification in the nextreaction.

To a suspension of the alcohol from above (˜3.7 mmol) and powdered 3 Åmolecular sieves (0.90 g) in CH₂Cl₂ (10 mL) was added 4-methylmorpholineN-oxide (0.696 g, 5.95 mmol) and tetrapropylammonium perruthenate (0.089g, 0.25 mmol) and the mixture stirred overnight. The reaction wasconcentrated under reduced pressure and purified by columnchromatography through a plug of silica gel (ethyl acetate/hexanes, 1:1)to afford the title compound (0.670 g, 84% over 2 steps) as a whitesolid. ¹H NMR (CDCl₃) δ 1.45 (br s, 9H), 1.64-1.73 (m, 2H), 2.21-2.27(m, 2H), 2.37-2.44 (m, 4H), 3.89-3.95 (m, 1H), 4.50 (br s, 1H), NH.

Following General Procedure B: To a stirred solution of8-amino-5,6,7,8-tetrahydroquinoline (195 mg, 1.32 mmol) and4-[N-(tert-butyloxycarbonyl)]amino-cyclohexanone (293 mg, 1.38 mmol) indry THF (5 mL) was added NaBH(OAc)₃ (392 mg, 1.85 mmol) and the mixturestirred for 2 h at room temperature. The reaction was diluted withCH₂Cl₂ (20 mL) and saturated aqueous sodium bicarbonate (40 mL) and theaqueous phase was washed with CH₂Cl₂ (2×10 mL). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated to afford thedesired secondary amine as a mixture of diastereomers (520 mg). Thediastereomers were separated and purified by column chromatography withsilica gel (CH₂Cl₂/MeOH, 96:4) to give a top, less polar diastereomer(179 mg, 39%) and a lower, more polar one (107 mg, 23%), each as anorange oil.

Following the General Procedure for N-alkylation: To a stirred solutionof the top, less polar diastereomer from above (179 mg, 0.52 mmol) inCH₃CN (5 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.04 mmol),KI (24 mg, 0.14 mmol) and1-(tert-butoxycarbonyl)-2-(chloromethyl)benzimidazole (149 mg, 0.56mmol). The mixture was stirred at 60° C. for 4 h then cooled, dilutedwith CH₂Cl₂ (40 mL) and saturated aqueous sodium bicarbonate (30 mL).The aqueous phase was washed with CH₂Cl₂ (2×10 mL), dried (Na₂SO₄),filtered and concentrated. Purification of the resultant brown oil bycolumn chromatography with silica gel (CH₂Cl₂/MeOH, 96:4) afforded thedesired alkylated cis-1,4-diamine,NM-(1-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-cis-1,4-diamine-4-carboxylicacid tert-butyl ester, (142 mg, 47%) as a yellow oil.

Using General Procedure D: Conversion of the oil from above (72 mg, 0.13mmol) to the hydrobromide salt with simultaneous removal of theN-tert-butoxycarbonyl protecting group followed by re-precipitation ofthe intermediate solid from methanol/ether gave COMPOUND 52 (67 mg, 82%)as an orange solid. ¹H NMR (D₂O) δ 1.66-1.81 (m, 4H), 1.85-2.08 (m, 4H),2.11-2.18 (m, 3H), 2.42-2.47 (m, 1H), 2.81-2.85 (m, 1H), 3.00-3.02 (m,2H), 3.53-3.55 (m, 1H), 4.45 (d, 1H, J=16.8 Hz), 4.57-4.63 (m, 1H), 4.60(d, 1H, J=16.8 Hz), 7.59 (dd, 2H, J=6.3, 3.3 Hz), 7.76 (dd, 2H, J=6.3,3.3 Hz), 7.80 (dd, 1H, J=7.8, 6.3 Hz), 8.28 (d, 1H, J=7.8 Hz), 8.58 (d,1H, J=5.5 Hz); ¹³C NMR (D₂O) δ 20.79, 23.38, 24.33, 25.64, 27.55, 27.70,27.90, 43.83, 46.55, 58.06, 59.77, 114.25, 125.82, 127.02, 130.95,139.12, 140.53, 147.99, 151.38, 152.14. ES-MS m/z 376 (M+H). Anal.Calcd. for C₂₃H₂₉N₅.2.9HBr.2.5H₂O: C, 42.16; H, 5.68; N, 10.69; Br,35.37. Found: C, 42.55; H, 5.43; N, 10.31; Br, 35.28.

Example 53

COMPOUND 53: PreparationN-{4-cis-[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-cyclohexyl}-2-chloro-benzamide(hydrobromide salt)

A solution of the diprotected amine from above,N¹-(1-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-cis-1,4-diamine-4-carboxylicacid tert-butyl ester, (see COMPOUND 52) (70 mg, 0.12 mmol) inCH₂Cl₂/TFA (1:1, 2 mL) was stirred at room temperature for 1.5 h. Thereaction was then concentrated and diluted with CH₂Cl₂ (15 mL) and 1 NNaOH (15 mL). The aqueous layer was washed with CH₂Cl₂ (2×10 mL) and thecombined organic extracts were dried (Na₂SO₄), filtered andconcentrated. To a solution of the resultant crude amine (32 mg) CH₂Cl₂(3 mL) was added Et₃N (0.045 mL, 0.32 mmol) and 2-chlorobenzoylchloride(0.030 mL, 0.24 mmol) and the mixture stirred overnight. The reactionwas diluted with CH₂Cl₂ (10 mL) saturated aqueous sodium bicarbonate (10mL). The aqueous layer was washed with CH₂Cl₂ (2×5 mL) and the combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated.Purification of the crude foam by radial chromatography on silica gelgel (1 mm plate, 100:1:1 CH₂Cl₂/MeOH/NH₄OH) afforded the title amide (23mg, 37% over 2 steps) as a yellow foam.

Using General Procedure D: Conversion of the foam from above (23 mg,0.045 mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 53 (27 mg, 83%) asa yellow solid. 1H NMR (D₂O) δ 1.44-1.62 (m, 4H), 1.74-1.97 (m, 4H),2.04-2.21 (m, 3H), 2.41-2.46 (m, 1H), 2.80-2.84 (m, 1H), 3.00-3.02 (m,2H), 3.98-3.99 (m, 1H), 4.41 (d, 1H, J=16.8 Hz), 4.55-4.60 (m, 1H), 4.58(d, 1H, J=16.8 Hz), 7.30-7.37 (m, 2H), 7.43-7.45 (m, 2H), 7.60 (dd, 2H,J=6, 3 Hz), 7.75 (dd, 2H, J=6, 3 Hz), 7.82 (dd, 1H, J=7.8, 6 Hz), 8.31(d, 1H, J=8.1 Hz), 8.58 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ 20.78, 23.87,25.39, 27.11, 27.59, 28.54, 28.92, 44.11, 45.77, 59.89, 60.00, 114.24,125.83, 127.07, 127.73, 128.61, 130.18, 130.88, 131.89, 135.36, 139.08,140.55, 148.01, 151.94, 152.11, 170.46. ES-MS m/z 514 (M+H). Anal.Calcd. for C₃₀H₃₂N₅OCl.2.2HBr.1.9H₂O: C, 49.61; H, 5.27; N, 9.64; Br,24.20. Found: C, 49.65; H, 5.22; N, 9.50; Br, 24.17.

Example 54

COMPOUND 54: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine(hydrobromide salt)

Following the General Procedure for N-alkylation: To a stirred solutionof the bottom, more polar diastereomer from above (see COMPOUND 52) (107mg, 0.31 mmol) in CH₃CN (5 mL) was added N,N-diisopropylethylamine (0.11mL, 0.63 mmol), KI (14 mg, 0.08 mmol) and1-(tert-butoxycarbonyl)-2-(chloromethyl)benzimidazole (106 mg, 0.40mmol) and the mixture was stirred at 60° C. for 7 h. Purification of theresultant brown oil by column chromatography with silica gel(CH₂Cl₂/MeOH/NH₄OH, 96:4:0 then 95:4:1) followed by radialchromatography on silica gel (1mm plate, (CH₂Cl_(2/)MeOH/NH₄OH, 50:1:1)afforded the desired alkylated trans-1,4-diamine (44 mg, 25%) as a clearoil.

Using General Procedure D: Conversion of the foam from above (31 mg,0.054 mmol) to the hydrobromide salt with simultaneous removal of theN-tert-butoxycarnoyl protecting group followed by re-precipitation ofthe intermediate solid from methanol/ether gave COMPOUND 54 (32 mg, 90%)as a white solid. ¹H NMR (D₂O) δ 1.40-1.61 (m, 4H), 1.86-2.30 (m, 7H),2.42-2.46 (m, 1H), 2.76-2.84 (m, 1H), 3.00-3.02 (m, 2H), 3.11-3.18 (m,1H), 4.44 (d, 1H, J=16.8 Hz), 4.52-4.57 (m, 1H), 4.57 (d, 1H, J=16.8Hz), 7.60 (dd, 2H, J=6, 3 Hz), 7.77 (dd, 2H, J=6, 3 Hz), 7.81 (dd, 1H,J=7.8, 6 Hz), 8.29 (d, 1H, J=7.8 Hz), 8.58 (d, 1H, J=5.7 Hz); ¹³C NMR(D₂O) δ 20.73, 24.05, 27.54, 27.62, 29.60, 29.74, 29.85, 44.06, 49.58,58.80, 59.30, 114.25, 125.80, 126.97, 131.03, 139.10, 140.46, 147.96,151.62, 152.09. ES-MS m/z 376 (M+H). Anal. Calcd. forC₂₃H₂₉N₅.3.0HBr.2.1H₂O: C, 42.11; H, 5.56; N, 10.67; Br, 36.54. Found:C, 42.24; H, 5.60; N, 10.51; Br, 36.50.

Example 55

COMPOUND 55: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-((S)-5,6,7,8-tetrahydro-quinolin-8-yl)-trans-cyclohexane-1,4-diamine(hydrochloride salt)

To a solution of trans-4-aminocyclohexanol hydrochloride (10.0 g, 65.9mmol) and triethylamine (18.4 mL, 132.0 mmol) in tetrahydrofuran (132mL) was added di-tert-butyl dicarbonate (15.31 g, 70.1 mmol). Themixture was stirred at 25° C. under nitrogen for 17 h at which timeethyl acetate (250 mL) was added. The solution was washed with water(2×100 mL), dried (Na₂SO₄) and concentrated to afford(4-Hydroxy-cyclohexyl)-carbamic acid tert-butyl ester as a white solid(13.82 g, 97%). ¹H NMR (CDCl₃) δ 1.09-1.25 (m, 2H), 1.31-1.39 (m, 2H),1.44 (s, 9H), 1.94-2.03 (m, 4H), 3.42 (bs, 1H), 3.56-3.64 (m, 1H), 4.34(bs, 1H).

To a solution of (4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester(5.80 g, 26.9 mmol) in dry methylene chloride (67 mL) was added in orderactivated 3 Å molecular sieves (6.54 g), 4-methylmorpholine N-oxide(5.04 g, 43.0 mmol) and tetrapropylammonium perruthenate (380 mg, 1.08mmol). The mixture was stirred at 25° C. for 18 h under nitrogen thenthe mixture was concentrated. Purification by column chromatography onsilica gel with hexane/ethyl acetate (1:1) afforded(4-oxo-cyclohexyl)-carbamic acid tert-butyl ester as a white solid (5.52g, 96%). ¹H NMR (CDCl₃) δ 1.46 (s, 9H), 1.64-1.74 (m, 2H), 2.21-2.27 (m,2H), 2.39-2.45 (m, 4H), 3.97 (bs, 1H), 4.40 (bs, 1H).

Acetic acid (2.9 mL, 50.7 mmol), (4-oxo-cyclohexyl)-carbamic acidtert-butyl ester (4.32 g, 20.2 mmol) and sodium triacetoxyborohydride(7.56 g, 35.7 mmol) were added to a solution of(S)-5,6,7,8-tetrahydro-quinolin-8-ylamine (2.86 g, 19.3 mmol) intetrahydrofuran (78 mL) and the mixture was stirred at 25° C. for 3.5 h.The mixture was diluted with methylene chloride (500 mL) and washed withsaturated sodium bicarbonate (600 mL). The aqueous layer was extractedwith methylene chloride (2×150 mL). The combine organic layers weredried (Na₂SO₄) and concentrated. The crude mixture of isomers waspurified by column chromatography on silica gel with methanol/methylenechloride (4:96) to afford the trans-isomer[4-((5)-5,6,7,8-tetrahydro-quinolin-8-ylamino)-trans-cyclohexyl]-carbamicacid tert-butyl ester as a white solid (2.01g, 30%). ¹H NMR (CDCl₃) δ1.06-1.39 (m, 4H), 1.69 (s, 9H) 1.65-1.80 (m, 2H), 1.90-2.14 (m, 5H),2.16-2.25 (m, 1H), 2.29 (bs, 1H), 2.56-2.71 (m, 1H), 2.72-2.88 (m, 2H),3.43 (bs, 1H), 3.92 (t, 1H, J=6.3 Hz), 4.39 (bs, 1H), 7.04 (dd, 1H,J=7.9, 4.5 Hz), 7.35 (d, 1H, J=7.5 Hz), 8.38 (d, 1H, J=4.5 Hz).

The enantiomeric purity of[4-((S)-5,6,7,8-tetrahydro-quinolin-8-ylamino)-trans-cyclohexyl]-carbamicacid tert-butyl ester was determined to be 95% by chiral HPLC using thefollowing conditions: Instrument: Hewlett Packard 1100 HPLC (VWD2);Column: ChiralPak AD, 2.1 cm×100 cm; Mobile Phases: A=90:10hexanes/isopropanol with 0.1%TFA, B=isopropanol; Isocratic: 90% A, 10%B;Total Run Time: 25 min; Flow Rate: 1.0 mL/min; Temperature: 10° C. ;Detector: UV @ 254 nm; Injection volume: 30 μL.

Retention time of the S enantiomer=5.3 min.

Retention time of the R enantiomer=8.1 min.

To a suspension of[4-((S)-5,6,7,8-tetrahydro-quinolin-8-ylamino)-trans-cyclohexyl]-carbamicacid tert-butyl ester (1.95g, 5.64 mmol) in dry acetonitrile (60 mL) wasadded 2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester(1.65g, 6.20 mmol), diisopropylethylamine (2.0 mL, 11.4 mmol) andpotassium iodide (100 mg, 0.60 mmol). The mixture was warmed to 60° C.and stirred for 2 days under nitrogen. The mixture was concentrated,dissolved in methylene chloride (80 mL) and washed with brine (50 mL).The aqueous layer was extracted with methylene chloride (3×50 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated. The crudemixture was purified by column chromatography on silica gel (80 g) withmethanol/methylene chloride (4:96) to afford2-{[(4-tert-butoxycarbonylamino-trans-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester as a white solid (1.82 g, 56%). ¹H NMR (CDCl₃) δ1.09 (bs, 2H), 1.43 (s, 9H), 1.68 (s, 9H), 1.83-2.14 (m, 6H), 2.47-2.63(m, 1H), 2.65-2.79 (m, 1H), 2.79-2.95 (m, 1H), 3.32 (bs, 1H), 4.30 (bs,2H), 4.46 (s, 2H), 6.75-6.89 (m, 1H), 7.00-7.13 (m, 1H), 7.61-7.70 (m,1H), 7.70-7.79 (m, 1H), 8.32 (bs, 1H).

2-{[(4-tert-Butoxycarbonylamino-trans-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester was dissolved in acetic acid (15 mL) and hydrogenchloride gas was bubbled through the solution for 10 min. The mixturewas stirred for an additional 1.75 h then diluted with acetic acid (15mL). The acetic acid solution was added dropwise, over 40 min., to arapidly stirred flask of diethyl ether (300 mL) where a white fluffyprecipitate formed. The ether mixture was allowed to settle anddecanted. The slurry was washed with ether (4×300 mL) and then theprecipitate was collected on a glass frit and rinsed thoroughly withether. The frit was placed into a vacuum oven (40° C.) for 18 h toafford COMPOUND 55 as a beige solid (1.36 g, 79%). ¹H NMR (D₂O) δ1.34-1.1.52 (m, 2H), 1.57 (dq, 2H, J=12.3, 2.4 Hz), 1.77-1.92 (m, 1H),1.97-2.21 (m, 6H), 2.24-2.42 (m, 1H), 2.82 (tt, 1H, J=11.6, 3.1 Hz),3.09 (d, 2H, J=3.9 Hz), 3.13 (tt, 1H, J=11.7, 3.6 Hz), 4.38 (d, 1H,J=16.5 Hz), 4.51 (m, 2H), 7.52-7.58 (m, 2H), 7.71-7.77 (m, 3H), 8.23 (d,1H, J=7.5 Hz), 8.54 (d, 1H, J=4.8 Hz); ¹³C NMR (D₂O) δ 20.70, 24.04,27.51, 27.62, 29.62, 29.67, 29.85, 44.05, 49.60, 58.74, 59.42, 114.30(2C), 125.64, 126.63 (2C), 131.62, 139.11, 140.28, 147.65, 151.75,152.19. ES-MS m/z 376 (M+H). Anal. Calcd. forC₂₃H₂₉N₅.3.0HCl.2.5H₂O.0.2Et₂O: C 52.47, H 7.22, N 12.86, Cl 19.52.Found: C 52.46, H 6.97, N 12.85, Cl 19.56.

The enantiomeric purity of COMPOUND 55 was determined to be 97% bychiral HPLC using the following conditions: Instrument: Hewlett Packard1100 HPLC (VWD2); Column: ChiralPak AD, 2.1 cm×100 cm; Mobile Phases:A=90:10 hexanes/isopropanol with 0.1%DEA, B=isopropanol; Isocratic: 70%A, 30%B; Total Run Time: 20 min; Flow Rate: 0.6 mL/min; Temperature: 5°C. ; Detector: UV @ 270 nm; Injection volume: 20 μL.

Retention time of the S enantiomer=11.1 min.

Retention time of the R enantiomer=8.8 min.

Example 56

COMPOUND 56: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-N²-benzyl-cyclohexane-trans-1,4-diamine(hydrobromide salt) Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine

Preparation of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine(Smith, J., Liras, J. L.: Schneider, S. E.; Anslyn, E J. Org. Chem.1996, 61, 8811-8818)

To a solution of trans-1,4-cyclohexanediamine (8.01 g, 70.1 mmol) inCHCl₃ (230 mL) was added a solution of di-tert-butyl dicarbonate (7.67g, 35.1 mmol) in CHCl₃ (50 mL) via syringe pump over a period of 6hours. The resultant white suspension was stirred at room temperaturefor an additional 10 hours then concentrated in vacuo and diluted withCH₂Cl₂ (100 mL) and saturated aqueous Na₂CO₃ (100 mL). The layers wereseparated and the organic layer was washed saturated aqueous Na₂CO₃(2×30 mL). The combined organic phases were dried (Na₂SO₄), filtered andconcentrated to give the title compound (5.30 g, 71% based on Boc₂O) asa white solid.

Following General Procedure for Reductive Amination B: To a stirredsolution of 6,7-dihydro-5H-quinolin-8-one (3.04 g, 20.65 mmol) andN-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine (4.42 g, 20.65 mmol)in dry THF (100 mL) was added AcOH (3 mL) and NaBH(OAc)₃ (5.69 g, 26.85mmol) and the mixture stirred overnight at room temperature.Purification by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,96:4:0 then 94:5:1) afforded the desired amine (3.79 g, 53%) as a whitesolid.

Following the general procedure for N-alkylation: To a stirred solutionof the trans-1,4-diamine from above (3.79 g, 11.0 mmol) in CH₃CN (55 mL)was added N,N-diisopropylethylamine (3.5 mL, 19.7 mmol), KI (91 mg, 0.55mmol) and 1-(tert-butoxycarbonyl)-2-(chloromethyl)benzimidazole (2.93 g,11.0 mmol) and the mixture was stirred at 60° C. overnight. Purificationof the resultant orange foam by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 96:4:0 then 94:5:1) afforded the desired alkylatedamine (3.28 g, 52%) as a yellow foam.

The yellow foam from above (3.28 g, 5.70 mmol) oil was dissolved inCH₂Cl₂/TFA (1:1, 10 mL) and the mixture stirred at room temperature for2.5 hours. The reaction was then concentrated and diluted with CH₂Cl₂(80 mL) and 1 N NaOH (75 mL). The aqueous layer was washed with CH₂Cl₂(2×50 mL) and the combined organic extracts were dried (Na₂SO₄),filtered and concentrated to afford the title compound (1.97 g, 92%) asa yellow foam. ¹H NMR (CDCl₃) δ 0.92-1.10 (m, 2H), 1.21-1.28 (m, 2H),1.45-1.58 (m, 4H), 1.66-1.77 (m, 2H), 1.82-1.90 (m, 2H), 1.95-2.09 (m,1H), 2.17-2.35 (m, 1H), 2.39-2.59 (m, 2H), 2.67-2.80 (m, 1H), 2.83-2.96(m, 1H), 4.10 (dd, 1H, J=9, 6 Hz), 4.19 (s, 2H), 7.14-7.21 (m, 4H), 7.43(d, 1H, J=6 Hz), 7.55-7.62 (br m, 2H), 8.60 (d, 1H, J=6 Hz); 13C NMR(CDCl₃) δ 21.85, 27.32, 29.31, 29.84, 30.97, 45.61, 50.03, 56.58, 62.37,110.77, 118.96, 121.36, 122.23, 134.74, 137.52, 146.34, 158.32, 158.60.

To a stirred solution ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine(140 mg, 0.37 mmol) in dry MeOH (3 mL) was added benzaldehyde (0.038 mL,0.37 mmol) and the solution stirred at room temperature for 3 h. Themixture was concentrated in vacuo, analyzed by 1H NMR and redissolved inMeOH (3 mL) and CH₂Cl₂ (0.8 mL). To this solution was added sodiumborohydride (28 mg, 0.74 mmol) and the mixture stirred for 2 h at roomtemperature. (see General Procedure B). Purification of the crudematerial by radial chromatography on silica gel gel (1 mm plate,CH₂Cl₂/MeOH/NH₄OH, gradient elution from 100:1:1 to 20:1:1) afforded thefree amine (119 mg, 69%) as a clear oil.

Using General Procedure D: Conversion of the oil from above (119 mg,0.26 mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 56 (149 mg, 79%) asa white solid. ¹H NMR (D₂O) δ 1.44-1.60 (m, 4H), 1.79-1.93 (m, 1H),2.00-2.11 (m, 1H), 2.14-2.32 (m, 5H), 2.40-2.44 (m, 1H), 2.77-2.85 (m,1H), 2.98-3.01 (m, 2H), 3.12-3.20 (m, 1H), 4.21 (s, 2H), 4.42 (d, 1H,J=16.8 Hz), 4.52-4.56 (m, 1H), 4.55 (d, 1H, J=16.8 Hz), 7.41-7.47 (m,5H), 7.59 (dd, 2H, J=6, 3 Hz), 7.76 (dd, 2H, J=6, 3 Hz), 7.79 (dd, 1H,J=8.1, 6.3 Hz), 8.28 (d, 1H, J=7.5 Hz), 8.57 (d, 1H, J=5.5 Hz); ¹³C NMR(D₂O) δ 20.72, 24.03, 27.54, 27.61, 28.08, 28.35, 29.71, 44.01, 48.93,56.04, 58.79, 59.32, 114.24, 125.80, 126.95, 129.72, 130.04, 131.06,131.31, 139.10, 140.46, 147.95, 151.56, 152.03. ES-MS m/z 466 (M+H).Anal. Calcd. for C₃₀H₃₅N₅.3.0HBr.2.0H₂O: C, 48.41; H, 5.69; N, 9.41; Br,32.20. Found: C, 48.65; H, 5.92; N, 9.32; Br, 31.97.

Example 57

COMPOUND 57: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N⁴-butyl-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-14-diamine(hydrobromide salt) Preparation ofN-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine^(ref)

^(ref)Smith, J.; Liras, J. L.; Schneider, S. E.; Anslyn, E. Solid andSolution Phase Organic Syntheses of Oligomeric Thioureas J. Org. Chem.1996, 61, 8811-8818.

To a solution of trans-1,4-cyclohexanediamine (8.01 g, 70.1 mmol) inCHCl₃ (230 mL) was added a solution of di-tert-butyl dicarbonate (7.67g, 35.1 mmol) in CHCl₃ (50 mL) via syringe pump over a period of 6hours. The resultant white suspension was stirred at room temperaturefor an additional 10 hours then concentrated under reduced pressure anddiluted with CH₂Cl₂ (100 mL) and saturated aqueous Na₂CO₃ (100 mL). Thelayers were separated and the organic layer was washed with saturatedaqueous Na₂CO₃ (2×30 mL). The combined organic phases were dried(Na₂SO₄), filtered, and concentrated to give the desired compound (5.30g, 71% based on Boc₂O) as a white solid.

Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine

Following General Procedure B: To a stirred solution of6,7-dihydro-5H-quinolin-8-one (3.04 g, 20.65 mmol) andN-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine (4.42 g, 20.65 mmol)in dry THF (100 mL) was added AcOH (3 mL) and NaBH(OAc)₃ (5.69 g, 26.85mmol) and the mixture stirred overnight at room temperature. Thereaction mixture was concentrated under reduced pressure, diluted withCH₂Cl₂ (100 mL) and saturated aqueous sodium bicarbonate (100 mL), andthe aqueous phase was extracted with CH₂Cl₂ (3×75 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered, and concentrated.Purification by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,96:4:0 then 94:5:1) afforded the desired amine (3.79 g, 53%) as a whitesolid.

Following the general procedure for N-alkylation: To a stirred solutionof [4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-trans-cyclohexyl]-carbamicacid tert-butyl ester from above (3.79 g, 11.0 mmol) in CH₃CN (55 mL)was added N,N-diisopropylethylamine (3.5 mL, 19.7 mmol), KI (91 mg, 0.55mmol) and 1-(tert-butoxycarbonyl)-2-(chloromethyl)benzimidazole (2.93 g,11.0 mmol). The mixture was stirred at 60° C. overnight, cooled,concentrated, diluted with CH₂Cl₂ (100 mL) and saturated aqueous sodiumbicarbonate (75 mL). The aqueous phase was washed with CH₂Cl₂ (2×50 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure.Purification of the resultant orange foam by column chromatography onsilica gel (CH₂Cl₂/MeOH/NH₄OH, 96:4:0 then 94:5:1) afforded the desiredalkylated amine (3.28 g, 52%) as a yellow foam.

The yellow foam from above (3.28 g, 5.70 mmol) was dissolved inCH₂Cl_(2/)TFA (1:1, 10 mL) and the mixture stirred at room temperaturefor 2.5 hours. The reaction was then concentrated and diluted withCH₂Cl₂ (80 mL) and 1 N NaOH (75 mL). The aqueous layer was washed withCH₂Cl₂ (2×50 mL) and the combined organic extracts were dried (Na₂SO₄),filtered, and concentrated to affordN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine(1.97 g, 92%) as a yellow foam. 1H NMR (CDCl₃) δ 0.92-1.10 (m, 2H),1.21-1.28 (m, 2H), 1.45-1.58 (m, 4H), 1.66-1.77 (m, 2H), 1.82-1.90 (m,2H), 1.95-2.09 (m, 1H), 2.17-2.35 (m, 1H), 2.39-2.59 (m, 2H), 2.67-2.80(m, 1H), 2.83-2.96 (m, 1H), 4.10 (dd, 1H, J=9, 6 Hz), 4.19 (s, 2H),7.14-7.21 (m, 4H), 7.43 (d, 1H, J=6 Hz), 7.55-7.62 (br m, 2H), 8.60 (d,1H, J=6 Hz); ³C NMR (CDCl₃) δ 21.85, 27.32, 29.31, 29.84, 30.97, 45.61,50.03, 56.58, 62.37, 110.77, 118.96, 121.36, 122.23, 134.74, 137.52,146.34, 158.32, 158.60.

To a stirred solution ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine(0.0753 g, 0.20 mmol) in anhydrous MeOH (2 mL) was added freshlydistilled butyraldehyde (22 μL, 0.24 mmol). The resultant mixture wasstirred at room temperature for 0.5 h and concentrated under reducedpressure. The residue was redissolved in anhydrous MeOH (2 mL) and NaBH₄(15 mg, 0.40 mmol) was added. The resultant mixture was stirred at roomtemperature for 22 hours. The mixture was concentrated and the residuewas partitioned between CH₂Cl₂ (20 mL) and saturated aqueous sodiumbicarbonate (30 mL). The phases were separated and the aqueous phase wasextracted with CH₂Cl₂ (2×15 mL). The combined organic extracts weredried (Na₂SO₄), filtered, and concentrated under reduced pressure.Purification of the crude material by radial chromatography on silicagel (TLC grade 1 mm plate, 100:1:1 CH₂Cl₂/CH₃OH/NH₄OH followed by 50:1:1CH₂Cl₂/CH₃OH/NH₄OH) provided 23 mg (30%) of the free base of the titlecompound as a pale yellow oil. Using General Procedure D: Conversion ofthe foam from above (23 mg, 0.05 mmol) to the hydrobromide salt followedby re-precipitation of the intermediate solid from methanol/ether gaveCOMPOUND 57 (73 mg, quantitative) as a white solid. ¹H NMR (D₂O) δ 0.88(t, 3H, J=7.5 Hz), 1.26-1.47 (m, 4H), 1.48-1.65 (m, 4H), 1.79-1.92 (m,1H), 1.93-2.34 (brm, 7H), 2.35-2.47 (m, 1H), 2.75-2.88 (m, 1H),2.95-3.14 (m, 5H), 4.42 (d, 1H, J=16.8 Hz), 4.49-4.55 (m, 1H), 4.56 (d,1H, J=16.5 Hz), 7.54-7.63 (m, 2H), 7.72-7.84 (m, 3H), 8.28 (d, 1H, J=7.5Hz), 8.56 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 13.17, 19.61, 20.71, 24.03,27.53, 27.59, 28.09, 28.20, 28.34, 29.69, 44.00, 45.15, 56.08, 58.78,59.39, 114.24, 125.79, 126.96, 131.06, 139.10, 140.46, 147.942, 151.58,152.05. ES-MS m/z 432 (M+H). Anal. Calcd. for C₂₇H₃₇N₅.3.0HBr.2.1H₂O: C,45.54; H, 6.26; N, 9.83; Br, 33.66. Found: C, 45.62; H, 6.07; N, 9.66;Br, 33.51.

Example 58

COMPOUND 58: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-N²,N²-dimethyl-cyclohexane-trans-1,4-diamine(hydrobromide salt)

To a stirred solution ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine(157 mg, 0.42 mmol) in dry MeOH (3 mL) was added paraformaldehyde(powder) (17 mg, 0.57 mmol) and the solution stirred at room temperaturefor 3 h. The mixture was concentrated in vacuo, analyzed by 1H NMR andredissolved in MeOH (2.5 mL) and CH₂Cl₂ (1 mL). To this solution wasadded sodium borohydride (32 mg, 0.83 mmol) and the mixture stirred for1.5 h at room temperature (see General Procedure A and B). Purificationof the crude material by radial chromatography on silica gel gel (1 mmplate, CH₂Cl₂/MeOH/NH₄OH, gradient elution from 50:1:1 to 10:1:1)afforded the dimethylated and monomethylated free amines (138 mg) as aninseparable yellow foam mixture. Repurification and separation of thetwo amines by column chromatography on basic alumina (CH₂Cl₂/MeOH, 98:2then 95:5) afforded the dimethylated product (44 mg, 26%) and themonomethylated free amine (21 mg, 13%), both as clear oils.

Using General Procedure D: Conversion of the dimethylated amine fromabove (44 mg, 0.11 mmol) to the hydrobromide salt followed byre-precipitation of the intermediate solid from methanol/ether gaveCOMPOUND 58 (72 mg, 97%) as a white solid. ¹H NMR (D₂O) δ 1.46-1.65 (m,4H), 1.79-1.93 (m, 1H), 2.05-2.21 (m, 5H), 2.31-2.53 (m, 2H), 2.75-2.82(m, 1H), 2.77 (s, 6H), 2.99-3.01 (m, 2H), 3.15-3.22 (m, 1H), 4.43 (d,1H, J=16.8 Hz), 4.50-4.55 (m, 1H), 4.56 (d, 1H, J=16.8 Hz), 7.58 (dd,2H, J=6, 3 Hz), 7.76 (dd, 2H, J=6, 3 Hz), 7.80 (dd, 1H, J=7.8, 6 Hz),8.28 (d, 1H, J=7.8 Hz), 8.57 (d, 1H, J=5.1 Hz); ¹³C NMR (D₂O) δ 20.71,23.97, 25.62, 25.82, 27.55, 27.76, 29.81, 40.05, 44.03, 58.87, 59.26,64.33, 114.24, 125.82, 127.01, 130.98, 139.12, 140.48, 148.00, 151.53,151.97. ES-MS m/z 404 (M+H). Anal. Calcd. for C₂₅H₃₃N₅.3.0HBr.2.0H₂O: C,44.01; H, 5.91; N, 10.26; Br, 35.13. Found: C, 44.14; H, 6.02; N, 10.01;Br, 34.98.

Example 59

COMPOUND 59: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-N²-methyl-cyclohexane-trans-1,4-diamine(hydrobromide salt)

Using General Procedure D: Conversion of the monomethylated amine fromabove (see COMPOUND 58) (21 mg, 0.054 mmol) to the hydrobromide saltfollowed by re-precipitation of the intermediate solid frommethanol/ether gave COMPOUND 59 (25 mg, 71%) as a white solid. ¹H NMR(D₂O) δ 1.31-1.43 (m, 2H), 1.51-1.63 (m, 2H), 1.78-1.93 (m, 1H),1.99-2.31 (m, 6H), 2.40-2.44 (m, 1H), 2.63 (s, 3H), 2.75-2.87 (m, 1H),2.98-3.01 (m, 3H), 4.42 (d, 1H, J=16.8 Hz), 4.51-4.55 (m, 1H), 4.55 (d,1H, J=16.8 Hz), 7.59 (dd, 2H, J=6, 3 Hz), 7.75 (dd, 2H, J=6, 3 Hz), 7.79(dd, 1H, J=7.8, 6 Hz), 8.28 (d, 1H, J=8.1 Hz), 8.56 (d, 1H, J=5.4 Hz);¹³C NMR (D₂O) δ 20.71, 24.01, 27.54, 27.85, 28.09, 29.63, 30.36, 44.00,57.11, 58.81, 59.40, 114.24, 125.78, 126.94, 131.09, 139.10, 140.45,147.93, 151.59, 152.05. ES-MS m/z 390 (M+H). Anal. Calcd. forC₂₄H₃₁N₅.2.9HBr.3.0H₂O: C, 42.50; H, 5.93; N, 10.33; Br, 34.17. Found:C, 42.48; H, 5.65; N, 10.12; Br, 34.31.

Example 60

COMPOUND 60: Preparation ofN-4-trans-[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-uinolin-8-yl)-amino]-cyclohexyl}-guanidine(hydrobromide salt)

To a solution ofN¹-(1H-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-N²-benzyl-cyclohexane-trans-1,4-diamine(174 mg, 0.46 mmol) in dry THF (1.5 mL) was added N.N′-bis-(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (TetrahedronLett. 1993, 34, 3389) and the resultant mixture was stirred at roomtemperature for 26 hours. The reaction was concentrated and purified byradial chromatography on silica gel (2 mm plate, CH₂Cl₂/MeOH/NH₄OH,gradient elution from 50:1:1 to 5:1:1) to afford the desired guanidine(51 mg, 18%) as a clear oil.

Using General Procedure D: Conversion of the oil from above (51 mg,0.083 mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 60 (50 mg, 85%) asa white solid. 1H NMR (D₂O) δ 1.22-1.34 (m, 2H), 1.49-1.60 (m, 2H),1.79-2.21 (m, 8H), 2.40-2.44 (m, 1H), 2.70-2.78 (m, 1H), 2.98-3.01 (m,2H), 3.24-3.32 (m, 1H), 4.42 (d, 1H, J=16.8 Hz), 4.50-4.55 (m, 1H), 4.56(d, 1H, J=16.8 Hz), 7.59 (dd, 2H, J=6, 3 Hz), 7.76 (dd, 2H, J=6, 3 Hz),7.80 (dd, 1H, J=7.8, 6 Hz), 8.28 (d, 1H, J=7.8 Hz), 8.57 (d, 1H, J=5.4Hz); ¹³C NMR (D₂O) δ 20.75, 24.04, 27.55, 28.14, 30.36, 31.23, 31.51,44.11, 50.20, 58.86, 59.67, 114.23, 125.78, 126.98, 130.97, 139.05,140.45, 147.94, 151.73, 152.23, 156.22. ES-MS m/z418 (M+H). Anal. Calcd.for C₂₄H₃₁N₇.3.0HBr.2.0H₂O.0.2C₄H₁₀O: C, 41.78; H, 5.68; N, 13.75; Br,33.62. Found: C, 41.74; H, 5.63; N, 13.62; Br, 33.65.

Example 61

COMPOUND 61: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N⁴-(1H-indol-3-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-14-diamine(free base)

General procedure B (Two step reductive amination): To a solution ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine(104 mg, 0.28 mmol) in CH₃OH (5 mL) was added indole-3-carboxaldehyde(52 mg, 0.36 mmol) and the resultant solution was stirred at roomtemperature overnight. NaBH₄ (26 mg, 0.68 mg) was added and the mixturewas stirred for an additional 15 minutes. The mixture was concentratedunder reduced pressure and the residue was partitioned between CH₂Cl₂(20 mL) and saturated aqueous NaHCO₃ (5 mL). The phases were separatedand the aqueous phase was extracted with CH₂Cl₂ (3×5 mL). The combinedorganic extracts were dried (Na₂SO₄) and concentrated. Purification ofthe crude material by radial chromatography on silica gel (1 mm plate,50:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided 105 mg of COMPOUND 61 as a whitefoam. ¹H NMR (CDCl₃) δ 0.93-1.30 (m, 3H), 1.47-2.02 (m, 9H), 2.20-2.25(m, 1H), 2.50-2.51 (m, 2H), 2.65-2.76 (m, 1H), 2.83-2.94 (m, 1H), 3.93(s, 2H), 4.10 (dd, 1H, J=5.7, 10.2 Hz), 4.20 (s, 2H), 7.07-7.12 (m, 2H),7.15-7.21 (m, 4H), 7.34 (d, 1H, J=7.8 Hz), 7.42-7.49 (m, 2H), 7.59 (d,1H, J=7.8 Hz), 7.66-7.69 (m, 1H), 8.23 (br s, 1H), 8.34 (br s, 1H), 8.60(d, 1H, J=3.6 Hz); ¹³C NMR (CDCl₃) δ 22.22, 27.63, 29.71, 30.34, 31.43,33.00, 33.14, 42.46, 46.01, 56.15, 57.61, 62.78, 111.30, 111.65, 115.35,119.00 (2 carbons), 119.78, 121.59, 121.88, 122.40, 122.60, 122.78,127.31, 134.03, 135.12, 136.78, 137.87, 145.03, 146.74, 158.77, 159.11.ES-MS m/z 505 (M+H). Anal. Calcd. for C₃₂H₃₆N₆.0.5 H₂O. 0.5CH₂Cl₂: C,70.19; H, 6.89; N, 15.11. Found: C, 69.94; H, 6.81; N, 15.15.

Example 62

COMPOUND 62: Preparation of N¹-(1H-Benzimidazol-2-ylmethyl)-N⁴-(pyridin-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine(hydrobromide salt)

Using General Procedure B (Two step reductive amination): Reaction ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine(98 mg, 0.26 mmol) with pyridine-2-carboxaldehyde (30 μL, 0.32 mmol) inCH₃OH (5 mL) for 2.5 hours and with NaBH₄ (27 mg, 0.71 mmol) for 15minutes followed by purification of the crude material by radialchromatography on silica gel (1 mm plate, 50:1:1 CH₂Cl₂—CH₃OH—NH₄OH)provided 79 mg (65%) of the free base of the title compound as acolorless oil.

Using General Procedure D: Conversion of the oil from above (79 mg, 0.17mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 62 (126 mg, 85%) asa white solid. ¹H NMR (D₂O) δ 1.45-1.63 (m, 4H), 1.79-1.93 (m, 1H),2.02-2.45 (m, 7H), 2.79-2.86 (m, 1H), 2.99-3.01 (m, 2H), 3.25-3.33 (m,1H), 4.41-4.60 (m, 5H), 7.56-7.61 (m, 2H), 7.75-7.82 (m, 5H), 8.22-8.30(m, 2H), 8.57 (d, 1H, J=5.1 Hz), 8.69 (d, 1H, J=4.5 Hz); ¹³C NMR (D₂O) δ20.71, 24.03, 27.55 (2carbons), 28.06, 28.31, 29.67, 43.99, 47.18,57.04, 58.78, 59.21, 114.22, 125.83, 126.41, 126.60, 127.03, 130.91,139.10, 140.51, 143.47, 146.81, 148.02, 148.03, 151.48, 151.97. ES-MSm/z 467 (M+H). Anal. Calcd. for C₂₉H₃₄N₆.4.2HBr.3.7H₂O: C, 39.89; H,5.26; N, 9.63; Br, 38.44. Found: C, 39.95; H, 5.19; N, 9.61; Br, 38.45.

Example 63

COMPOUND 63: Preparation of1-N′-[trans-4-(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-cyclohexanyl-N,N-dimethylformamidine(hydrobromide salt)

Using the procedure of L. Cai (Y. Han and L. Cai Tetrahedron Lett. 1997,38(31), 5423-5426) a solution of 2-pyridinesulfonyl chloride (71 mg,0.40 mmol) in DMF (1 mL) was stirred for 10 minutes at room temperature.N-(1H-Benzimidazol-2-ylmethyl)-N]-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine(100 mg, 0.267 mmol) was then added, and the mixture was stirred at roomtemperature for 2 hours. The DMF was then removed in vacuo, and theresidue was taken up in dichloromethane and washed sequentially with asaturated aqueous sodium carbonate solution, followed by distilledwater. The organic fraction was then dried over anhydrous sodium sulfateand concentrated. The residue was purified by silica gel flashchromatography to afford two products:1-N′-[trans-4-(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-cyclohexanyl-N,N-dimethylformamidine(52 mg (45%)), andN-(1H-benzimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine-N-(2-pyridinyl)-sulfonamide(41 mg, 29%). The spectral data for the formamidine is as follows: 1HNMR (CDCl₃) δ 1.41 (m, 2H), 1.56 (m, 2H), 1.67 (m, 2H), 1.79-1.91 (m,3H), 2.21 (m, 1H), 2.51 (m, 1H), 2.74-2.81 (m, 3H), 2.83 (s, 6H), 4.06(dd, 1H, J=8.1, 5.4 Hz), 4.17 (s, 2H), 7.16 (m, 5H), 7,41 (d, 1H, J=8.1Hz), 7.44 (br s, 1H (NH)), 7.68 (br s, 1H), 8.58 (d, 1H, J=4.8 Hz). Thesulfonamide showed an excessive broadening of resonances in the ¹H NMRspectrum (in CDCl₃), so it was not characterized fully at this stage,and was instead taken directly to the salting reaction.

1-N¹-[trans-4-(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-cyclohexanyl-N,N-dimethylformamidine(52 mg, 0.120 mmol) was taken up in acetic acid (1 mL), to which asaturated solution of HBr in acetic acid (1 mL) was added. The mixturewas then stirred, precipitated and isolated as per procedure D to yieldCOMPOUND 63 as a white crystalline (36 mg). 1H NMR (D₂O). δ 1.45 (m,4H), 1.82-2.20 (m, 7H), 2.42(m, 1H), 3.74 (dd, 1H, J=10.5, 11.1 Hz),2.94 (s, 3H), 2.99 (m, 2H), 3.16 (s, 3H), 3.33 (m, 1H), 4.41 (d, 1H,J=15.3 Hz), 4.52 (d, 1H, J=15.3 Hz), 4.54 (m, 1H), 7.58 (m, 2H), 7.75(m, 2H), 7.77 (s, 1H), 7.80 (dd, 1H, J=8.1, 5.7 Hz), 8.28 (d, 1H, J=8.1Hz), 8.56 (d, 1H, J=5.7 Hz). ¹³C NMR (D₂O) δ 20.73, 24.04, 27.54, 28.10,30.34, 32.07, 32.32, 36.05, 43.21, 44.11, 56.62, 58.79, 59.36, 114.21,125.78, 126.99, 130.92, 139.03, 140.45, 147.99, 151.68, 152.19, 155.22.ES-MS m/z 431 (M+H); Anal. Calcd. for (C₂₆H₃₄N₆×2.9 HBr×2.7 H₂O): C,43.74; H, 5.97; N, 11.77; Br 32.46. Found: C, 43.81; H, 5.70; N, 11.44;Br, 32.39.

Example 64

COMPOUND 64: Preparation ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine-N-(2-pyridinyl)-sulfonamide

N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine-N-(2-pyridinyl)-sulfonamide(from the above reaction, 41 mg, 0.079 mmol) was taken up in acetic acid(1 mL), to which a saturated solution of HBr in acetic acid (1 mL) wasadded. The mixture was then stirred, precipitated and isolated as perprocedure D to yield COMPOUND 64 as a white crystalline solid (52 mg).¹H NMR (D₂O) δ 1.20-2.16 (series of m, 9H), 2.38 (m, 1H), 2.60 (m, 1H),2.82 (m, 1H), 2.98 (m, 2H), 3.10 (m, 1H), 3.62 (m, 1H), 4.46 (d, 1H,J=15.3 Hz), 4.49 (m, 1H), 4,51 (d, 1H, J=15.3 Hz), 7.56 (m, 2H), 7.73(m, 3H), 7.94 (m, 1H), 8.06 (m, 1H), 8.26 (m, 1H), 8.56 (m, 2H). C NMR(D₂O) δ 20.70, 27.51, 28.25, 30.44, 32.47, 44.04, 49.31, 52.58, 58.81,59.48, 114.18, 122.92, 125.74, 126.97, 128.47, 130.87, 138.98, 140.25,140.38, 147.90, 150.28, 151.72, 152.19. ES-MS m/z 517 (M+H); Anal.Calcd. for (C₂₈H₃₂N₆O₂S×2.6 HBr×3.3 H₂0): C, 42.76; H, 5.28; N, 10.69;Br 26.42. Found: C, 42.86; H, 5.07; N, 10.32; Br, 26.77.

Example 65

COMPOUND 65: Preparation of N¹-(1H-benzimidazol-2-ylmethyl)-N⁴-(1H-indol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydroquinolin-8-yl)-cylcohexane-1,4-diaminePreparation of 2-hydroxymethylindole

To a solution of indole-2-carboxylic acid (485 mg, 3.01 mmol) in THF (20mL), cooled to 0° C. under nitrogen, was added a suspension of LiA1H₄(248 mg, 6.2 mmol) in THF (6 mL). The resultant green suspension wasstirred at room temperature for 4 hours. The reaction was quenched byslow addition of an 80% aqueous MeOH solution (1.0 mL) and the solventwas evaporated under reduced pressure. The residue was suspended in MeOHand filtered through Celite, rinsing with MeOH. Concentration of thefiltrate under reduced pressure gave a yellow oil. Purification by flashcolumn chromatography on silica (MeOH/CH₂Cl₂, 19:1 then 9:1) gave thealcohol as a beige solid (357 mg, 2.43 mmol, 81%). ¹H NMR (CDCl₃) δ 1.85(t, 1H, J=6.0 Hz), 4.83 (d, 2H, J=6.0 Hz), 6.42 (d, 1H, J=1.5 Hz), 7.11(td, 1H, J=6.9, 1.5 Hz), 7.20(td, 1H, J=6.9, 1.5 Hz), 7.35 (dd,1H,J=6.9, 1.5 Hz), 7.59(d, 1H, J=6.9 Hz), 8.33 (br s., 1H).

Preparation of indole-2-carboxaldehyde

To a solution of the alcohol (341 mg, 2.32 mmol) in CH₂Cl₂ (12 mL) wasadded activated MnO₂ (2.40 g, 22.1 mmol). The suspension was stirred atroom temperature for 2.5 hours, then was diluted with CH₂Cl₂ and suctionfiltered through Celite. The filtrate was concentrated under reducedpressure affording the crude aldehyde as an orange solid (288 mg, 1.98mmol, 86%). ¹H NMR (CDCl₃) δ 7.18 (td, 1H, J=6.9,1.5 Hz), 7.29 (d, 1H,J=1.5 Hz), 7.37-7.50 (m, 2H), 7.76 (d, 1H, J=6.9 Hz), 9.18 (br s., 1H),9.86 (s, 1H).

Preparation of COMPOUND 65

A solution of the aldehyde (74 mg, 0.51 mmol) andN¹-(1H-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydroquinolin-8-yl)-cylcohexane-1,4-diamine(189 mg, 0.50 mmol) in MeOH (5 mL) was stirred at room temperature undernitrogen for 20 hours. NaBH₄ (39 mg, 1.0 mmol) was added and thereaction was stirred for another 20 minutes. The solvent was evaporatedunder reduced pressure, and the residue was dissolved into CH₂Cl₂ (50mL) washing with saturated aqueous NaHCO₃ (5 mL) and brine (5 mL). Theorganic solution was dried (MgSO₄), filtered and concentrated underreduced pressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1) gave COMPOUND 65 as a light yellow solid(118 mg, 0.23 mmol, 47%). ¹H NMR (CDCl₃) δ 0.88-1.13 (m, 2H), 1.16-1.29(m, 1H), 1.39-1.52 (m, 1H), 1.63-1.73 (m, 1H), 1.80-2.04 (m, 6H),2.19-2.23 (m, 1H), 2.33-2.41 (m, 1H), 2.44-2.52 (m, 1H), 2.67-2.74 (m,1H), 2.81-2.94 (m, 1H), 3.91 (s, 2H), 4.09 (dd, 1H, J=9.9, 5.9 Hz), 4.18(s, 2H), 6.27 (s, 1H), 7.02-7.21 (m, 5H), 7.28 (d, 1H, J=10.2 Hz), 7.43(d, 1H, J=7.8 Hz), 7.45-7.48 (m, 1H), 7.52 (d, 1H, J=7.8 Hz), 7.66-7.69(m, 1H), 8.60 (d, 1H, J=4.2 Hz), 8.69 (br s., 1H). ¹³C NMR (CDCl₃) δ21.8, 27.3, 29.3, 29.9, 31.0, 32.7, 32.9, 44.4, 45.7, 56.1, 57.2, 62.1,99.6, 110.6, 110.9, 118.6, 119.5, 120.0, 121.2, 121.3, 121.5, 122.2,128.5, 133.6, 134.7, 135.8, 137.4, 138.3, 144.6, 146.4, 158.4, 158.5.ES-MS m/z 505 (M+H). Anal. Calcd. for C₃₂H₃₆N₆.CH₂Cl₂.0.1H₂O: C, 67.07;H, 6.51; N, 14.22. Found: C, 67.34; H, 6.55; N, 14.23.

Example 66

COMPOUND 66: Preparation ofcis-(1H-benzimidazol-2-ylmethyl)-(4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

Cis-(4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-aminewas prepared as described for COMPOUND 67. ¹H NMR (CDCl₃) δ 1.61-1.75(m, 12H), 1.85-1.92 (m, 1H), 2.01-2.18 (m, 1H), 2.54 (t, 4H, J=4.5 Hz),2.76-2.81 (m, 2H), 2.92 (br m, 1H), 3.74 (t, 4H, J=4.5 Hz), 3.87-3.93(m, 1H), 7.03-7.07 (m, 1H), 7.36 (d, 1H, J=9.0 Hz), 8.39 (d, 1H, J=6.0Hz).

The above amine (69.0-mg, 0.22 mmol),2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (70.0mg, 0.26 mmol), N,N-diisopropylethylamine (50 μL, 0.28 mmol), andpotassium iodide (3.7 mg, 0.02 mmol) in CH₃CN (1.5 mL) were stirred at60° C. overnight. The reaction mixture was cooled to room temperatureand the solvent was removed under reduced pressure. Purification of thecrude material by radial chromatography on silica gel (1 mm plate,NH₄OH/MeOH/CH₂Cl₂, 1:1:98 then 1:2:97) afforded the desired compound(56.8 mg, 47%) as a pale yellow solid. ¹H NMR (CDCl₃) δ 1.30-1.34 (m,2H), 1.45-1.66 (m, 11H), 1.88-2.01 (m, 4H), 2.05-2.16 (m, 4H), 2.40 (brm, 4H), 2.54 (t, 1H, J=4.4 Hz), 2.59 (t, 1H, J=3.9 Hz), 2.68-2.73 (m,1H), 3.04-3.11 (m, 1H), 3.61-3.71 (m, 4H), 4.29 (dd, 1H, J=8.7, 5.7 Hz),4.43 (s, 2H), 6.829 (dd, 1H, J=7.5, 4.8 Hz), 7.07 (d, 1H, J=6.9 Hz),7.22-7.28 (m, 2H), 7.61-7.70 (m, 1H), 7.73-7.79 (m, 1H), 8.32 (dd, 1H,J=4.8, 1.5 Hz).

To a solution of the above solid (56.8 mg, 0.10 mmol) in acetic acid (1mL) was added a solution of hydrobromic acid in acetic acid (0.5 mL) andthe reaction mixture was stirred for 1 hour. The diethyl ether was addeduntil a precipitation of COMPOUND 67 was afforded as a pale yellow solid(49.1 mg, 62%). ¹H NMR (D₂O) δ 1.75-1.89 (m, 6H), 2.12-2.36 (m, 8H),2.98-3.99 (m, 4H), 3.11 (br m, 2H), 3.31 (br t, 2H), 3.64 (br m, 2H),3.91 (m, 2H), 4.07 (br m, 2H), 7.565 (dd, 2H, J=6.0, 3.2 Hz), 7.72-7.77(m, 3H), 8.24 (d, 1H, J=7.8 Hz), 8.52 (d, 1H, J=6.0 Hz). ¹³C NMR (D₂O) δ20.73, 23.37, 24.35, 24.46, 25.70, 27.50, 43.76, 50.48, 57.69, 59.40,63.50, 63.78, 114.25, 125.73, 126.91, 131.23, 139.12, 140.44, 147.84,151.29, 152.19. ES-MS m/z 446 [M+H]+. Anal. Calcd. forC₂₇H₃₅N₅O.3.0HBr.2.0H₂O: C, 44.83; H, 5.71; N, 9.68; Br, 33.14. Found:C, 44.88; H, 5.72; N, 9.49; Br, 33.13.

Example 67

COMPOUND 67: Preparation oftrans-(1H-Benzimidazol-2-ylmethyl)-(4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt) Preparation of(4-morpholin-4-yl-cyclohexylamine)-carbamic acid tert-butyl ester

To a solution of (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester (426mg, 2.00 mmol) and morpholine (175 μL, 2.00 mmol) in CH₂Cl₂ (25 mL) andacetic acid (120 μL) was added sodium triacetoxyborohydride (636 mg,3.00 mmol) and the mixture was stirred at room temperature overnight.The mixture was concentrated under reduced pressure and diluted withsaturated aqueous sodium carbonate (30 mL). The aqueous layer was washedwith CH₂Cl₂ (4×20 mL), and the combined organic extracts were dried(MgSO₄), filtered, and concentrated under reduced pressure. Purificationby flash column chromatography on silica gel (MeOH/CH₂Cl₂, 1:9) affordedthe title compound as a white solid (76.2 mg, 13%). ¹H NMR (CDCl₃) δ1.04-1.17 (m, 6H), 1.25-1.38 (m, 4H), 1.44 (s, 9H), 1.93 (d, 2H, J=12.0Hz), 2.07 (d, 2H, J=12.0 Hz), 2.12-2.17 (m, 2H), 3.25-3.36 (br m, 1H),4.35 (br m, 1H), 4.81 (br d, 1H).

Preparation of 4-morpholin-4-yl-cyclohexylamine

To a solution of the acetamine from above (60.7 mg, 0.21 mmol) in CH₂Cl₂(2 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirredat room temperature for 1 hour. The solvent was removed under reducedpressure and the residue was taken up in NaOH (10 N) plus an equalvolume of water. The aqueous layer was washed with CH₂Cl₂ (5×10 mL), andthe combined organic extracts were dried (MgSO₄), filtered, andconcentrated under reduced pressure to afford the product as anoff-white solid (33.5 mg, 85%). ¹H NMR (CDCl₃) δ 1.08-1.27 (m, 4H), 1.39(s, 2H), 1.88 (dd, 1H, J=10.5, 2.4 Hz), 2.16 (tt, 1H, J=11.3, 3.2 Hz),2.53 (t, 4H, J=4.7 Hz), 2.61 (tt, 4H, J=10.8, 3.6 Hz), 3.69 (t, 4H,J=4.5 Hz).

Preparation oftrans-(4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

The above amine (50.2 mg, 0.27 mmol) and 6,7-dihydro-5H-quinolin-8-one(40.1 mg, 0.27 mmol) in MeOH (2 mL) were stirred at room temperatureovernight to form the imine. To the above solution was added sodiumborohydride (20.6 mg, 0.544 mmol) and the mixture was stirred for anadditional 2 hour. The solvent was removed under reduced pressure and tothe residue was added CH₂Cl₂ and NaOH (0.5 N) until basic. The mixturewas extracted with CH₂—Cl₂ (3×15 mL), and the combined organic extractswere dried (MgSO₄), filtered, and concentrated under reduced pressure.Purification by radial chromatography on silica gel (1 mm plate, CH₂Cl₂then NH₄OH/CH₂Cl₂, 1:99) afforded the desired amine (35.9 mg, 42%) as ayellow oil. ¹H NMR (CDCl₃) δ 1.24-1.29 (m, 2H), 1.71-1.74 (m, 2H),1.95-2.16 (m, 8H), 2.56 (t, 3H, J=4.5 Hz), 2.75-2.79 (m, 2H), 3.41 (s,2H), 3.71 (t, 4H, J=4.5 Hz), 3.92 (t, 1H, J=6.0 Hz), 7.02-7.06 (m, 1H),7.35 (d, 1H, J=9.0 Hz), 8.37 (d, 1H, J=3.0 Hz).

Preparation oftrans-2-{[(4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester

The above amine (35.9 mg, 0.11 mol),2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (36.7mg, 0.14 mmol), N,N-diisopropylethylamine (25 μL, 0.14 mmol), andpotassium iodide (1.8 mg, 0.01 mmol) were stirred in CH₃CN (1 mL) at 60°C. overnight. The reaction mixture was cooled to room temperature andthe solvent was removed under reduced pressure. Purification of thecrude material by radial chromatography on silica gel (1 mm plate,CH₂Cl₂ then NH₄OH/CH₂Cl₂, 1:99) afforded the desired compound (33.7 mg,54%) as a yellow oil. ¹H NMR (CDCl₃) δ 1.13-1.36 (m, 3H), 1.49-1.68 (m,11H), 1.89-1.97 (m, 4H), 2.02-2.14 (m, 4H), 2.49-2.52 (m, 4H), 2.59 (brt, 1H), 2.67-2.84 (m, 2H), 3.68 (t, 4H, J=4.5 Hz), 4.24 (t, 1H, J=6.0Hz), 4.44 (d, 2H, J=6.0 Hz), 6.834 (dd, 1H, J=7.5, 4.7 Hz), 7.08 (d, 1H,J=6.3 Hz), 7.22-7.25 (m, 2H), 7.34-7.69 (m, 1H), 7.71-7.78 (m, 1H), 8.32(dd, 1H, J=4.5, 1.2 Hz).

Preparation of(S)-(1H-Benzimidazol-2-ylmethyl)-(4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

To a solution of the above oil (33.7 mg, 0.062 mmol) in acetic acid (1.5mL) was added a solution of hydrobromic acid in acetic acid (1 mL) andthe reaction mixture was stirred for 1 hour. The diethyl ether was addeduntil a precipitation of COMPOUND 67 was afforded as a pale yellow solid(28.9 mg, 63%). ¹H NMR (D₂O) δ 1.48-1.61 (m, 4H), 1.82-1.88 (m, 2H),2.07-2.39 (m, 6H), 2.75-2.81 (br t, 2H), 2.99 (br d, 2H, J=4.5 Hz), 3.19(t, 2H, J=10.7 Hz), 3.44 (br d, 2H, J=12.3 Hz), 3.76 (br td, 2H, J=12.3Hz), 4.09 (br d, 2H, J=11.7 Hz), 4.39-4.57 (m, 3H), 7.59 (dd, 2H, J=6.3,3.2 Hz), 7.74-7.77 (m, 3H), 8.27 (d, 1H, J=7.8 Hz), 8.55 (d, 1H, J=5.7Hz). ¹³C NMR (D₂O) δ 20.68, 23.95, 25.72, 25.93, 27.52, 27.80, 29.81,43.97, 49.29, 58.82. 59.19, 64.38, 64.77, 114.23, 125.79, 126.96,131.07, 139.11, 140.45, 147.95, 151.53, 151.95. ES-MS m/z 446 [M+H]⁺,468 [M+Na]⁺. Anal. Calcd. For C₂₇H₃₅N₅O.3.0HBr.3.0H₂O: C, 43.68; H,5.97; N, 9.43; Br, 32.29. Found: C, 43.72; H, 5.76; N, 9.25; Br, 32.06.

Example 68

COMPOUND 68: Preparation ofN-(1H-benzoimidazol-2-ylmethyl)-N′-pyrimidin-2-ylmethyl-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-transcyclohexane-1,4-diamine(hydrobromidesalt) Preparation of pyrimidine-2-carboxylic acid methyl ester

To a saturated HCl(g)/MeOH solution (40 mL) was added a solution of2-cyanopyrimidine (1.97 g, 18.7 mmol) in MeOH (6 mL) at 0° C. Thesolution was stirred at room temperature for 30 minutes then poured intodiethyl ether (200 mL) to give a colourless precipitate that wascollected by filtration. The crude material was dissolved in H₂O (50mL), adjusted to pH 4 using saturated NaHCO₃(aq) and 10% HCl(aq) thenextracted with CHCl₃ (5×25 mL). The combined organic extracts werewashed with saturated NaHCO₃(aq) (25 mL) then dried (MgSO₄) andconcentrated in vacuo to give a colourless solid (1.49 g, 58%). ¹H NMR(CDCl₃) δ 4.08 (s, 3H), 7.51 (t, 1H, J=5.1 Hz), 8.96 (d, 2H, J=5.1 Hz).

To a solution of pyrimidine-2-carboxylic acid methyl ester (243 mg, 1.76mmol) in THF (17 mL) at −78° C. was added LiAlH₄ (1.0 M/THF, 0.47 mL,0.47 mmol) over 30 minutes, and the solution was stirred at −78° C. for15 minutes. Acetic acid (0.25 mL, 4.4 mmol) was added dropwise, and thesolution was allowed to warm to room temperature then concentrated invacuo. The residue was dissolved in H₂O (15 mL), adjusted to pH 4 using10% HCl(aq) then extracted with CHCl₃ (4×10 mL). The combined organicextracts were washed with saturated NaHCO₃(aq) (20 mL) then dried(MgSO₄) and concentrated in vacuo to give a yellow liquid (156 mg). Thecrude material was determined by ¹H NMR to be a mixture ofpyrimidine-2-carbaldehyde, pyrimidine-2-carboxylic acid methyl ester,and THF (1.0:1.7:7.7 respectively) and was used in the next step withoutfurther purification.

Using General Procedure B: To a solution of the crude aldehyde fromabove (156 mg) andN-(1H-benzoimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,4-diamine(68 mg, 0.18 mmol) in THF (2 mL) was added NaBH(OAc)₃ (114 mg, 0.538mmol) and the mixture was stirred at room temperature for 1.5 h. Thecrude material was dissolved in saturated HBr/AcOH (2 mL) and stirred atroom temperature for 5 minutes. The solution was made basic with 10 NNaOH(aq) and extracted with CH₂Cl₂ (3×15 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. Purification ofthe crude material by column chromatography on silica gel (200:5:1CH₂Cl₂/MeOH/NH₄OH) afforded a colourless oil (50 mg).

Using General Procedure D: Conversion of the oil from above (50 mg, 0.11mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 68 (78 mg, 85%) asa colourless solid. ¹H NMR (D₂O) δ 1.58 (m, 4H), 1.89 (m, 1H), 2.03-2.45(m, 7H), 2.84 (m, 1H), 3.00 (m, 2H), 3.30 (m, 1H), 4.42-4.60 (m, 5H),7.50 (t, 1H, J=5.1 Hz), 7.58 (m, 2H), 7.78 (m, 3H), 8.29 (d, 1H, J=8.1Hz), 8.58 (d, 1H, J=5.7 Hz), 8.79 (d, 2H, J=5.1 Hz); ¹³C NMR (D₂O) δ20.73, 24.04, 27.56, 28.08 28.33, 29.73, 44.05, 48.59, 56.44, 58.80,59.26, 114.24, 121.65, 125.84, 127.02, 130.91, 139.12, 140.51, 148.03,151.51, 152.00, 158.38, 160.98. ES-MS m/z 468 (M+H). Anal. Calcd. forC₂₈H₃₃N₇.3.9HBr.3.2H₂O.0.2C₄H₁₀O: C, 40.43; H, 5.34; N, 11.46; Br,36.42. Found: C, 40.37; H, 5.05; N, 11.35; Br, 36.58.

Example 69

COMPOUND 69: Preparation ofN-(1H-Benzoimidazol-2-ylmethyl)-1-methyl-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-trans-cyclohexane-1,4-diamine(hydrobromide salt) Preparation oftrans-(4-Cyano-4-diallylamino-cyclohexyl)-carbamic acid tert-butyl ester

To a stirred solution of (4-Oxo-cyclohexyl)-carbamic acid tert-butylester (3.07 g, 14.4 mmol) and diallylamine (1.78 mL, 14.4 mmol) inanhydrous ClCH₂CH₂Cl (25 mL) was added titanium(IV) isopropoxide (4.28mL, 14.4 mmol) at 0° C. The reaction mixture was allowed to warm to roomtemperature and was stirred overnight. The mixture was then cooled to 0°C. and diethylaluminum cyanide (1M in toluene, 17 ml, 17 mmol) was addedwith vigorous stirring. The reaction was allowed to warm to roomtemperature and stirred an additional 3.5 hours, after which are addedCH₂Cl₂ (30 mL), EtOAc (40 mL), and celite (3 g). The reaction mixturewas cooled to 0° C., water (8 mL) was added slowly with vigorousstirring and, after an additional 5 minutes of stirring at roomtemperature, the excess water was quenched with Na₂SO₄. The finalmixture was then filtered over celite, concentrated under reducedpressure, and subjected to flash chromatography over silica gel(Hexanes/EtOAc, 4:1) to afford the desired nitrile (3.11 g, 68% over 2steps) as a pale yellow oil. ¹H NMR (CDCl₃) δ 1.44 (s, 9H), 1.53-1.59(m, 3H), 1.78-1.99 (m, 2H), 2.07 (d, 2H, J=9 Hz), 2.28 (d, 2H, J=12Hz),3.33 (t, 4H, J=4.5 Hz), 3.37-3.55 (br m, 1H), 4.33-4.53 (br m, 1H),5.12-5.24 (m, 4m), 5.82-5.94 (m, 2H).

Preparation of trans-(4-Diallylamino-4-methyl-cyclohexyl)-carbamic acidtert-butyl ester

To a solution of the nitrile from above (3.11 g, 9.7 mmol) in anhydrousTHF (30 mL) at 0° C. was added dropwise methylmagnesium bromide (3.0 Min Et₂O, 10.0 mL, 29.2 mmol). After the addition, the reaction wasallowed to warm to RT and stirred overnight. The reaction was thenquenched with saturated aqueous NaHCO₃ (50 mL), diluted with EtOAc (30mL), and the layers separated. The aqueous layer was extracted withEtOAc (1×20 mL) and CH₂Cl₂ (1×20 mL). The combined organic extracts weredried (Na₂SO₄), filtered, and concentrated under reduced pressure toafford a crude mixture of the desired product (19%) andN-(4-Diallylamino-4-methyl-cyclohexyl)-acetamide (72%). The resultantcrude, yellow oil (1.21 g) was used without further purification in thenext step.

Preparation of trans-N,N-Diallyl-1-methyl-cyclohexane-1,4-diamine

To a stirred solution of the crude mixture from above in dry CH₂Cl₂ (4mL) was added TFA (4 mL) and the reaction stirred at RT for 2.5 h. Thereaction mixture was diluted with CH₂Cl₂ (30 mL) and concentrated underreduced pressure. The residue was diluted with CH₂Cl₂ (50 mL) and washedwith 1N NaOH (1×40 mL) and the aqueous phase extracted with CH₂Cl₂ (2×25mL). The combined organic extracts were dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to afford a yellow oil (0.840 g, 12%desired amine).

The byproduct from above,N-(4-Diallylamino-4-methyl-cyclohexyl)-acetamide (0.1979 g, 0.79 mmol),was dissolved in 6N HCl (6 mL) and refluxed for 6 h. The reaction wascooled to RT and made basic with 10N NaOH and extracted with CH₂Cl₂(3×20 mL). The combined organic extracts were dried (Na₂SO₄), filtered,and concentrated under reduced pressure to give the desired primaryamine (0.1063 g, 65%) as a yellow/green oil, which was used withoutfurther purification in the next reaction.

Preparation of2-{[trans-(4-Amino-4-methyl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester

Following General Procedure B: To a stirred solution of6,7-dihydro-5H-quinolin-8-one (0.0895 g, 0.61 mmol) and the crudeN,N-Diallyl-1-methyl-cyclohexane-1,4-diamine from above (0.1063 g, 0.51mmol) in dry THF (5 mL) was added AcOH (5 drops) and NaBH(OAc)₃ (0.1805g, 0.85 mmol) and the mixture stirred overnight at room temperature.Purification by column chromatography on silica gel (CH₂Cl₂MeOH/NH₄OH,96:4:0 then 95:4:1) afforded the desired amine (75.2 mg, 36%) as acolourless oil.

Following the general procedure for N-alkylation: To a stirred solutionof the combined amines from above (0.1842 g, 0.54 mmol) in CH₃CN (4 mL)was added N,N-diisopropylethylamine (0.17 mL, 0.98 mmol), KI (4.5 mg,0.027 mmol) and 1-(tert-butoxycarbonyl)-2-(chloromethyl)benzimidazole(0.1449 g, 0.54 mmol). The mixture was stirred at 60° C. overnight.Purification of the resultant orange oil by column chromatography onsilica gel (CH₂Cl₂/MeOH/NH₄OH, 96:4:0 then 89:10:1) afforded the desiredalkylated amine (0.1364 g, 44%) as a orange foam.

To a stirred solution of the alkylated amine from above (0.1364 g, 0.24mmol) in dry CH₂Cl₂ (4 mL) was added N,N-dimethylbarbituric acid (0.1869g, 1.2 mmol) and and tetrakis(triphenylphosphine)-palladium(0) (0.028 g,0.024 mmol) and the mixture stirred at room temperature for 64 h. Thereaction was diluted with CH₂Cl₂ (20 mL) and saturated aqueous NaHCO₃(30 mL). The phases were separated and the aqueous layer extracted withCH₂Cl₂ (2×20 mL). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated under reduced pressure. Purification of thecrude material by radial chromatography on silica gel (2 mm plate,CH₂Cl₂/MeOH/NH₄OH, 50: 1:1 then 25: 1:1) afforded the desired amine(28.9 mg, 25%) and the monoallyl-protected amine (51.0 mg, 40%).

Preparation of2-{[trans-(4-tert-Butoxycarbonylamino-4-methyl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester

To a stirred solution of the desired primary amine (28.9 mg, 0.059 mmol)from above in dry THF (1.5 mL) was added Di-tert-butyl dicarbonate (47mg, 0.22 mmol) and the mixture stirred at room temperature overnight.The reaction was concentrated under reduced pressure and the residue waspurified by radial chromatography on silica gel (1 mm plate,CH₂Cl₂/MeOH/NH₄OH, 100:1:1) to afford the protected amine (25 mg, 71%)as a colourless oil.

Using General Procedure D: Conversion of the oil from above (25 mg,0.042 mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 69 (23 mg, 82%) asa white solid. ¹H NMR (D₂O) δ 1.29 (s, 3H), 1.56-1.78 (m, 4H), 1.79-2.04(m, 4H), 2.07-2.27 (m, 3H), 2.38-2.48 (m, 1H), 2.77-2.83 (m, 1H), 2.99(d, 2H, J=5.4 Hz); 4.42 (d, 1H, J=16.5 Hz), 4.58 (d, 1H, J=16.8 Hz),4.54-4.61 (m, 1H), 7.56-7.61 (m, 2H), 7.72-7.81 (m, 3H), 8.27 (d, 1H,J=7.8 Hz), 8.55 (d, 1H, J=5.1 Hz); ¹³C NMR (D₂O) δ 20.71, 24.24, 26.56,26.86, 27.50, 34.87, 35.05, 43.78, 53.48, 58.03, 59.84, 114.21, 125.76,126.97, 131.05, 139.08, 140.46, 147.91, 151.38, 152.11.ES-MS m/z390(M+H). Anal. Calcd. for C₂₄H₃₁N₅.2.9HBr.3.1H₂O: C, 42.39; H, 5.94; N,10.30; Br, 34.08. Found: C, 42.30; H, 5.69; N, 10.11; Br, 34.18.

Example 70

COMPOUND 70: Preparation ofN¹-Allyl-N-(1H-Benzoimidazol-2-ylmethyl)-1-methyl-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-trans-cyclohexane-1,4-diamine(hydrobromide salt)

Repurification of the monoallyl-protected amine (51 mg, 0.10 mmol) fromabove by radial chromatography on silica gel (1 mm plate,CH₂Cl₂/MeOH/NH₄OH, 100:1:1 then 50:1:1 then 25:1:1) afforded themonoallyl-protected amine (24.6 mg, 20%) as an orange oil.

Using General Procedure D: Conversion of the oil from above (25 mg,0.047 mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 70 (32 mg, 94%) asan off-white solid. ¹H NMR (D₂O) δ 1.29 (s, 3H), 1.55-1.95 (br m, 7H),2.01-2.22 (m, 6H), 2.38-2.45 (m, 1H), 2.77-2.86 (m, 1H), 2.97-3.02 (m,2H), 3.65 (d, 2H, J=6.9 Hz), 4.43 (d, 1H, J=16.8 Hz), 4.57 (d, 1H,J=16.8 Hz), 4.59-4.65 (m, 1H), 5.44 (d, 1H, J=16.2 Hz), 5.48 (d, 1H,J=23.1 Hz), 5.86-6.00 (m, 1H), 7.56-7.62 (m, 2H), 7.72-7.81 (m, 3H),8.27 (d, 1H, J=7.8 Hz), 8.55 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 14.52(Et₂O), 20.70, 23.66, 24.11, 24.33, 26.08, 27.49, 33.48, 33.85, 43.72,44.50, 66.47 (Et₂O), 114.20, 123.96, 125.78, 127.03, 128.43, 130.95,139.08, 140.51, 147.95, 151.28, 152.12. ES-MS m/z 430 (M+H). Anal.Calcd. for C₂₇H₃₅N₅.3.0HBr.2.9H₂O: C, 44.76; H, 6.09; N, 9.67; Br,33.08. Found: C, 45.00; H, 5.96; N, 9.61; Br, 32.72.

Example 71

COMPOUND 71: Preparation ofN-(1H-Benzoimidazol-2-ylmethyl)-1-phenyl-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-trans-cyclohexane-1,4-diamine(hydrobromide salt) Preparation oftrans-(4-Cyano-4-diallylamino-cyclohexyl)-carbamic acid tert-butyl ester

To a stirred solution of (4-Oxo-cyclohexyl)-carbamic acid tert-butylester (3.55 g, 16.6 mmol) and diallylamine (2.05 mL, 16.6 mmol) inanhydrous ClCH₂CH₂Cl (30 mL) was added titanium(IV) isopropoxide (4.95mL, 16.6 mmol) at 0° C. The reaction mixture was allowed to warm to roomtemperature and was stirred overnight. The mixture was then cooled to 0°C. and diethylaluminum cyanide (1M in toluene, 19.6 ml, 19.6 mmol) wasadded with vigorous stirring. The reaction was allowed to warm to roomtemperature and stirred an additional 5 h, after which were added CH₂Cl₂(40 mL), EtOAc (40 mL), and celite (4 g). The reaction mixture wascooled to 0° C., water (10 mL) was added slowly with vigorous stirringand, after an additional 5 minutes of stirring at room temperature, theexcess water was quenched with Na₂SO₄. The final mixture was thenfiltered over celite, concentrated under reduced pressure, and subjectedto flash chromatography over silica gel (Hexanes/EtOAc, 4:1) to affordthe desired nitrile (2.62 g, 66% over 2 steps) as a pale yellow oil. ¹HNMR (CDCl₃) δ 1.44 (s, 9H), 1.50-1.70 (m, 4H), 1.77-1.99 (m, 2H), 2.07(d, 2H, J=9 Hz), 2.28 (d, 2H, J=12 Hz), 3.33 (t, 4H, J=6.0 Hz),4.33-4.53 (br m, 1H), 5.11-5.24 (m, 4H), 5.82-5.95 (m, 2H).

Preparation of trans-(4-Diallylamino-4-phenyl-cyclohexyl)-carbamic acidtert-butyl ester

To a solution of the nitrile from above (1.00 g, 3.1 mmol) in anhydrousTHF (16 mL) at 0° C. was added dropwise phenylmagnesium bromide (3.0 Min Et₂O, 3.1 mL, 9.4 mmol). After the addition, the reaction was allowedto warm to RT and stirred for 3 h. The reaction was then quenched withsaturated aqueous NH₄Cl (40 mL), diluted with EtOAc (30 mL), and thelayers separated. The aqueous layer was extracted with EtOAc (1×20 mL)and CH₂Cl₂ (1×20 mL). The combined organic extracts were dried (Na₂SO₄),filtered, and concentrated under reduced pressure. Purification bycolumn chromatography on silica gel (Hexanes/EtOAc, 4:1) afforded boththe desired product (0.2057 g, 32%) andN-(4-Diallylamino-4-phenyl-cyclohexyl)-benzamide (0.11 g, 17%) as whitesolids.

Preparation of trans-N,N-Diallyl-1-phenyl-cyclohexane-1,4-diamine

To a stirred solution of the desired product (0.2057 g, 0.56 mmol) fromabove in dry CH₂Cl₂ (2 mL) was added TFA (2 mL) and the reaction stirredat RT for 4 h. The reaction mixture was diluted with CH₂Cl₂ (15 mL) andconcentrated under reduced pressure. The residue was diluted with CH₂Cl₂(20 mL) and washed with 1N NaOH (1×30 mL) and the aqueous phaseextracted with CH₂Cl₂ (2×20 mL). The combined organic extracts weredried (Na₂SO₄), filtered, and concentrated under reduced pressure toafford a yellow oil (0.1055 g, 70%). The resultant amine was usedwithout further purification in the next reaction.

The byproduct from above,trans-N-(4-Diallylamino-4-phenyl-cyclohexyl)-benzamide (0.4558 g, 1.22mmol), was dissolved in a solution of H₂O (2.5 mL), 6N HCl (3.5 mL) andTHF (2 mL) and refluxed overnight. The reaction was cooled to RT,diluted with H₂O (15 mL) and made basic with 10N NaOH after which theaqueous solution was extracted with CH₂Cl₂ (3×20 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered, and concentrated underreduced pressure. Purification by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 96:4:0 then 89:10:1) afforded the desired primaryamine (80 mg, 24%) as a yellow oil.

Preparation of2-{[trans-(4-Amino-4-phenyl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester

Following General Procedure B (Stepwise Reductive Amination UsingNaBH₄): To a stirred solution of 6,7-dihydro-5H-quinolin-8-one (0.099 g,0.67 mmol) and N,N-Diallyl-1-phenyl-cyclohexane-1,4-diamine (0.181 g,0.48 mmol) in dry MeOH (3 mL) was added NaBH₄ (0.051 g, 1.3 mmol) after2 h and the mixture stirred for an additional 2 h at room temperature.Purification by radial chromatography on silica gel (2 mm plate,CH₂Cl₂/MeOH/NH₄OH, 100:1:1 then 75:1:1) afforded the desired amine (150mg, 56%) as a pale yellow oil.

Following the general procedure for N-alkylation: To a stirred solutionof the the amine from above (0.150 g, 0.37 mmol) in CH₃CN (2 mL) wasadded N,N-diisopropylethylamine (0.12 mL, 0.67 mmol), KI (3 mg, 0.019mmol) and 1-(tert-butoxycarbonyl)-2-(chloromethyl)benzimidazole (0.099g, 0.37 mmol). The mixture was stirred at 60° C. overnight. Purificationof the resultant beige foam by radial chromatography on silica gel (2 mmplate, CH₂C₂/MeOH/NH₄OH, 100:1:1 then 50:1:1) afforded the desiredalkylated amine (0.149 g, 64%) as a yellow oil.

To a stirred solution of the alkylated amine (0.149 g, 0.24 mmol) fromabove in dry CH₂Cl₂ (2.5 mL) was added N,N-dimethylbarbituric acid(0.1841 g, 1.2 mmol) and Tetrakis(triphenylphosphine)-palladium(0)(0.068 g, 0.06 mmol) and the mixture stirred at room temperature for 64h. The reaction was diluted with CH₂Cl₂ (20 mL) and saturated aqueousNaHCO₃ (30 mL). The phases were separated and the aqueous layerextracted with CH₂Cl₂ (2×20 mL). The combined organic extracts weredried (Na₂SO₄), filtered and concentrated under reduced pressure.Purification of the crude material by radial chromatography on silicagel (2 mm plate, CH₂Cl₂/MeOH/NH₄OH, 50:1:1 then 25:1:1 then 20:1:1)afforded the deprotected amine (28.9 mg, 25%) and themonoallyl-protected amine (70.1.0 mg, 54%, 90% purity).

Preparation of2-{[trans-(4-tert-Butoxycarbonylamino-4-phenyl-cyclohexyl)-(5,6,7,8-tetrahydro-guinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester:

To a stirred solution of the desired primary amine (28.9 mg, 0.13 mmol)from above in dry THF (2 mL) was added Di-tert-butyl dicarbonate (42 mg,0.19 mmol) and the mixture stirred at room temperature overnight. Thereaction was concentrated under reduced pressure and the residue waspurified by radial chromatography on silica gel (1 mm plate,CH₂Cl₂/MeOH/NH₄OH, 100:1:1 the 50:1: 1) to afford the boc-protectedamine (34 mg, 44%) as a colourless oil.

Using General Procedure D: Conversion of the oil from above (24 mg,0.037 mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 71 (24 mg, 85%) asa beige solid. ¹H NMR (D₂O) δ 1.80-1.99 (m, 3H), 2.00-2.27 (m, 5H),2.28-2.53 (m, 4H), 2.89-3.04 (m, 3H), 4.47 (d, 1H), J=16.8 Hz), 4.61 (d,1H, J=16.5 Hz), 4.60-4.68 (m, 1H), 7.40-7.53 (m, 5H), 7.55-7.61 (m, 2H),7.71-7.81 (m, 3H), 8.26 (d, 1H, J=7.2 Hz), 8.55 (d, 1H, J=5.1 Hz); ¹³CNMR (D₂O), δ 20.74, 24.26, 24.54, 26.75, 27.53, 34.29, 34.46, 43.85,57.40, 58.08, 59.61, 114.24, 125.12, 125.79, 126.97, 129.40, 129.64,131.08, 139.14, 140.51, 140.91, 147.94, 151.34, 152.04. ES-MS m/z 452(M+H). Anal. Calcd. for C₂₉H₃₃N₅.2.7HBr.5.3H₂O: C, 45.50; H, 6.10; N,9.15; Br, 28.18. Found: C, 45.43; H, 5.43; N, 8.93; Br, 28.23.

Example 73

COMPOUND 73(R) and (S): Preparation of the two diastereomers ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohex-2-ene-trans-14-diamine

Cis-1-acetoxy-4-chloro-2-cyclohexene was prepared from1,3-cyclohexadiene following the procedure reported by Backvall et al(J. Am. Chem. Soc. 1985, 107, 3676-3686.).

To a stirred solution of cis-1-acetoxy-4-chloro-2-cyclohexene (6.87 g,39.4 mmol) in DMF (160 mL) was added sodium azide (5.29 g, 81.1 mmol)and the resultant mixture was stirred at room temperature for 2 hours.The reaction mixture was poured into brine (160 mL) and diluted withdiethyl ether (300 mL) and water (80 mL). The phases were separated andthe organic phase was washed with brine (5×50 mL). The organic phase wasdried (MgSO₄), and concentrated to provide 6.13 g (85%) oftrans-1-acetoxy-4-azido-2-cyclohexene as a pale red oil which was usedwithout further purification.

A mixture of trans-1-acetoxy-4-azido-2-cyclohexene (6.13 g, 33.9 mmol),Lindlar's catalyst (1.18 g), and di-tert-butyl dicarbonate (11.35 g,52.1 mmol) in methanol (170 mL) was hydrogenated under atmosphericpressure for 19 hours. The mixture was filtered through Celite® and thecake was washed with methanol. The filtrate was concentrated and theresultant oil was purified by column chromatography on silica gel (6:1hexanes-ethyl acetate) and provided 6.70 g (77%) oftrans-1-acetoxy-4-(tert-butoxycarbonylamino)-2-cyclohexene as a whitesolid.

To a solution oftrans-1-acetoxy-4-(tert-butoxycarbonylamino)-2-cyclohexene (6.70 g, 26.3mmol) in methanol (130 mL) was added solid K₂CO₃ (7.50 g, 54.4 mmol) andthe mixture was stirred at room temperature for 1 hour. The reactionmixture was concentrated and the residue was dissolved in CH₂Cl₂ (250mL) and saturated aqueous NaHCO₃ (100 mL). The phases were separated andthe aqueous phase was extracted with CH₂Cl₂ (3×50 mL). The combinedorganic extracts were dried (Na₂SO₄) and concentrated. Purification ofthe crude material by column chromatography on silica gel (20:1CH₂Cl₂—CH₃OH) provided 3.38 g (60%) oftrans-1-hydroxy-4-(tert-butoxycarbonylamino)-2-cyclohexene as a whitesolid. 1H NMR (CDCl₃) δ 1.44 (s, 9H), 1.52-1.57 (m, 1H), 2.05-2.14 (m,3H), 4.20-4.26 (br s, 2H), 4.45 (br s, 1H), 4.47-4.60 (m, 1H), 5.70 (d,1H, J=10.2 Hz), 5.81 (d, 1H, J=10.2 Hz);

To a mixture oftrans-1-hydroxy-4-(tert-butoxycarbonylamino)-2-cyclohexene (2.93 g, 13.8mmol) in hexachloroacetone (70 mL) was added triphenylphosphine (7.51 g,28.6 mmol) and the mixture was stirred at room temperature for 1 hour.The mixture was concentrated and the thus obtained oil was purified bycolumn chromatography on silica gel (10:1 hexanes-ethyl acetate) andprovided 1.98 g (62%) ofcis-1-(tert-butoxycarbonylamino)-4-chloro-2-cyclohexene as a yellowsolid.

To a stirred solution ofcis-1-(tert-butoxycarbonylamino)-4-chloro-2-cyclohexene (1.85 g, 8.00mmol) in DMF (40 mL) was added sodium azide (1.17 g, 18.0 mmol) and theresultant mixture was stirred at room temperature for 16 hours. Thereaction mixture was poured into brine (40 mL) and diluted with ethylacetate (120 mL) and water (20 mL). The phases were separated and theorganic phase was washed with brine (4×25 mL). The organic phase wasdried (MgSO₄), and concentrated. Purification of the crude material bycolumn chromatography on silica gel (10:1 hexanes-ethyl acetate)provided 1.14 g (60%) oftrans-1-azido-4-(tert-butoxycarbonylamino)-2-cyclohexene as a colorlessoil.

To a solution oftrans-1-azido-4-(tert-butoxycarbonylamino)-2-cyclohexene (1.14 g, 4.79mmol) in THF (50 mL) and water (5 mL) was added triphenylphosphine (2.60g, 10 mmol) and the mixture was stirred at room temperature for 20hours. The mixture was concentrated and the thus obtained material waspurified by column chromatography on silica gel (10:1:1CH₂Cl₂—CH₃OH—NH₄OH) followed by radial chromatography on silica gel (2mm plate, 100:1:1 CH₂Cl₂—CH₃OH—NH₄OH) and provided 0.32 g (31%) oftrans-1-amino-4-(tert-butoxycarbonylamino)-2-cyclohexene as a colorlessoil. ¹H NMR (CDCl₃) δ 1.44 (s, 9H), 1.50-1.92 (m, 2H), 1.99-2.10 (m,2H), 3.32 (br s, 1H), 4.10-4.19 (m, 1H), 4.47-4.60 (m, 1H), 5.57-5.77(m, 2H);

Using General Procedure B: Reaction oftrans-1-amino-4-(tert-butoxycarbonylamino)-2-cyclohexene (0.222 g, 1.05mmol) and 6,7-dihydro-5H-quinolin-8-one (0.304 g, 2.06 mmol) in THF (10mL) with NaBH(OAc)₃ (0.423 g, 2.00 mmol) for 4 hours followed bypurification of the crude material by column chromatography on silicagel (25:1 CH₂Cl₂—CH₃OH) provided 0.277 g (77%) ofN¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-N⁴-(tert-butoxycarbonyl)-cyclohex-2-ene-trans-1,4-diamineas a yellow foam.

Using the General Procedure for N-alkylation: A solution ofN¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-N⁴-(tert-butoxycarbonyl)-cyclohex-2-ene-trans-1,4-diamine(0.277 g, 0.81 mmol),1-tert-(butoxycarbonyl)-2-(chloromethyl)benzimidazole (0.327 g, 1.22mmol), catalytic potassium iodide (14 mg), and N,N-diisopropylethylamine(0.28 mL, 1.61 mmol) in CH₃CN (8 mL) was heated at 60° C. for 20 hours.Purification of the crude material by column chromatography on silicagel (20:1:1 CH₂Cl₂-MeOH—NH₄OH) followed by radial chromatography onsilica gel (1 mm plate, 100:1:1 CH₂Cl₂-MeOH—NH₄OH) provided twodiasteriomers ofN¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-N¹-(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-N⁴-(tert-butoxycarbonyl)-cyclohex-2-ene-trans-1,4-diamine,129 mg (28%) of a white foam and 18 mg (4%) of a white solid.

General Procedure D: Conversion of the major diastereomer (100 mg) tothe hydrobromide salt with simultaneous removal of the BOC-protectinggroups, followed by re-precipitation of the intermediate solid frommethanol/ether, gave COMPOUND 73(R) (103 mg, 88%) as a white solid. ¹HNMR (D₂O) δ 1.45-1.57 (m, 1H), 1.70-1.82 (m, 2H), 2.00-2.17 (m, 4H),2.48-2.52 (m, 1H), 2.93 (br d, 2H, J=5.1 Hz), 3.61-3.63 (m, 1H),3.88-3.91 (m, 1H), 4.38-4.46 (m, 2H), 4.55 (d, 1H, J=16.8 Hz), 5.88 (brd, 1H, J=10.5 Hz), 6.25 (d, 1H, J=10.5 Hz), 7.52-7.57 (m, 2H), 7.69-7.77(m, 3H), 8.22 (d, 1H, J=8.1 Hz), 8.55 (d, 1H, J=5.1 Hz; ¹³C NMR (D₂O) δ20.63, 23.56, 27.14, 27.30, 27.52, 42.75, 47.46, 56.83, 60.11, 114.17,125.84, 127.00, 128.66, 130.94, 133.97, 139.22, 140.59, 147.98, 151.38,151.46; ES-MS m/z 374 (M+H). Anal. Calcd. for C₂₃H₂₇N₅.3.0HBr.2.9H₂O: C,41.33; H, 5.40; N, 10.48; Br, 35.86. Found: C, 41.14; H, 5.15; N, 10.28;Br, 36.10.

General Procedure D: Conversion of the minor diastereomer (18 mg) to thehydrobromide salt with simultaneous removal of the BOC-protectinggroups, followed by re-precipitation of the intermediate solid frommethanol/ether, gave COMPOUND 73(S) (15 mg, 68%) as a white solid. ¹HNMR (D₂O) δ 1.45-1.56 (m, 1H), 1.73-1.90 (m, 2H), 2.03-2.37 (m, 5H),2.96(d, 2H, J=4.8 Hz), 3.66-3.70 (m, 1H), 3.89-3.91 (m, 1H), 4.34-4.46(m, 2H), 4.52 (d, 1H, J=16.2 Hz), 5.75 (d, 1H, J=10.25 Hz), 6.05 (d, 1H,J=10.2 Hz), 7.53-7.56 (m, 2H), 7.70-7.76 (m, 3H), 8.22 (d, 1H, J=7.8Hz), 8.52 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ 20.56, 24.42, 25.14, 27.03,27.40, 43.22, 47.65, 57.18, 58.39, 114.24, 125.76, 126.90, 128.40,131.22, 135.51, 139.13, 140.42, 147.75, 150.87, 152.02; ES-MS m/z 374(M+H). Anal. Calcd. for C₂₃H₂₇N₅.3.0HBr.3.1H₂O: C, 41.10; H, 5.43; N,10.42; Br, 35.67. Found: C, 41.38; H, 5.09; N, 10.35; Br, 35.36.

Example 74

COMPOUND 74: Preparation of(Z)-N′-(1H-Benzimidazol-2-ylmethyl)-N′-(5,7,8-tetrahydro-quinolin-8-yl)-but-2-ene-1,4-diaminePreparation of ((Z)-4-Chloro-but-2-enyl)-carbamic acid tert-butyl ester

To a stirred suspension of (Z)-4-chloro-2-butenylamine hydrochloride(1.0 g, 7.0 mmol) in THF (35 mL) and water (0.2 mL) was addedN,N-diisopropylethylamine (2.7 mL, 15.4 mmol) followed by di-tert-butyldicarbonate (1.8 g, 8.4 mmol). The resultant solution was stirred for 3h, at which time saturated aqueous sodium bicarbonate (20 mL) anddiethyl ether (40 mL) were added. The phases were separated and theaqueous layer was extracted with Et₂O (3×30 mL). The combined organicextracts were washed once with brine (20 mL), dried (MgSO₄), andconcentrated in vacuo. Purification of the crude material by flashchromatography (silica gel, 4:1 hexane-EtOAc) afforded 1.3 g (90%) ofthe title compound as a white solid. ¹H NMR (CDCl₃) δ 1.44 (s, 9H), 3.82(t, 2H, J=6 Hz), 4.12 (d, 2H, J=9 Hz), 4.62 (br s, 1H), 5.60-5.70 (m,1H), 5.72-5.77 (m, 1H).

Following the General Procedure for N-alkylation: To a solution of(1H-N-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(200 mg, 0.53 mmol) and ((Z)-4-chloro-but-2-enyl)-carbamic acidtert-butyl ester (130 mg, 0.64 mmol) in CH₃CN (3 mL) were addedN,N-diisopropylethylamine (138 μL, 0.80 mmol) and KI (4.4 mg, 0.027mmol) and the reaction stirred at 60° C. for 18 h. The crude materialwas taken up in neat TFA (1 mL) and stirred 3 h. Saturated aqueoussodium bicarbonate (5 mL) was cautiously added, and the resultingmixture was extracted with CH₂Cl₂ (3×10 mL) then the combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo.Purification of the crude material by radial chromatography (1 mm plate,50:1:1 CH₂Cl₂-MeOH—NH₄OH) afforded the title compound (57 mg, 31%) as awhite solid. ¹H NMR (CDCl₃) δ 1.68-1.72 (m, 1H), 1.84-2.05 (m, 2H),2.15-2.22 (m, 1H), 2.71 (dt, 1H, J=17, 5 Hz), 2.84 (ddd, 1H, J=16, 10, 5Hz), 3.15-3.26 (m, 3H), 3.38 (dd, 1H, J=14, 7 Hz), 3.97-4.12 (m, 3H),5.46-5.54 (m, 2H), 7.13 (dd, 1H, J=8, 5 Hz), 7.16-7.21 (m, 2H), 7.40(dd, 1H, J=7, 1 Hz), 7.57 (br s, 2H), 8.57 (dd, 1H, J=5, 1 Hz); ¹³C NMR(CDCl₃) δ 21.0, 22.9, 28.9, 37.4, 46.4, 48.6, 60.5, 115.0, 121.8, 122.2,130.7, 131.6, 134.6, 137.4, 146.6, 154.2, 156.8. ES-MS m/z 348 (M+H).Anal. Calcd. for C₂₁H₂₅N₅.0.1CHCl₃.0.8CH₄O: C, 68.32; H, 7.41; N, 18.19.Found: C, 68.60; H, 7.05; N, 17.82.

Example 75

COMPOUND 75: Preparation of2-{4-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-(E)-but-2-enyl}-isoindole-1,3-dione

Preparation of2-{[[(Z)-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-but-2-enyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester

Following the General Procedure for N-alkylation,(1H-N-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(293 mg, 0.77 mmol) and (E)-N-(4-bromo-2-butenyl)phthalimide (preparedas described by Norman, M. H.; Minick, D. J.; Rigdon, G. C. J. Med.Chem. 1996, 39, 149-157) (260 mg, 0.93 mmol) were converted into thecorresponding alkylation product using the following quantities ofreagents and solvents: diisopropylethylamine (202 μL, 1.16 mmol), CH₃CN(4 mL). The reaction time in this case was 18 h, while the reactiontemperature was 40° C. The resulting crude material was purified byflash chromatography (silica gel, 20:2:1 CH₂Cl₂—MeOH—NH₄OH) to provide360 mg (81%) of2-{[[(Z)-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-but-2-enyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester. ¹H NMR (CDCl₃) δ 1.67 (s, 9H), 1.68-1.70 (m, 1H),1.79-1.91 (m, 1H), 1.93-2.04 (m, 1H), 2.14-2.19 (m, 1H), 2.59-2.79 (m,2H), 3.33-3.48 (m, 2H), 4.00 (d, 2H, J=6 Hz), 4.25 (dd, 1H, J=10, 6 Hz),4.42 (d, 1H, J=16 Hz), 4.60 (d, 1H, J=16 Hz), 5.29-5.57 (m, 1H),5.65-5.74 (m, 1H), 6.95 (dd, 1H, J=7, 5 Hz), 7.17-7.25 (m, 3H),7.63-7.72 (m, 3H), 7.74-7.80 (m, 3H), 8.37 (d, 1H, J=4 Hz).

2-{[[(Z)-4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-but-2-enyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (150 mg, 0.26 mmol) was taken up in neat TFA (2mL) and stirred 3 h. Saturated aqueous sodium bicarbonate (10 mL) wascautiously added, and the resulting mixture was extracted with CH₂Cl₂(3×10 mL) then the combined organic extracts were dried (MgSO₄), andconcentrated in vacuo. Purification of the crude material thus obtainedby radial chromatography (silica gel, 1 mm plate, 50:1:1CH₂Cl₂—MeOH—NH₄OH) afforded 102 mg (81%) of COMPOUND 75 as a whitesolid. ¹H NMR (CDCl₃) δ 1.66-1.71 (m, 1H), 1.84-1.97 (m, 2H), 2.13-2.15(m, 1H), 2.66-2.79 (m, 2H), 3.22-3.26 (m, 2H), 3.99-4.07 (m, 3H),4.13-4.16 (m, 2H), 5.67-5.71 (m, 2H), 7.10 (dd, 1H, J=8, 5 Hz),7.14-7.20 (m, 2H), 7.36 (dd, 1H, J=8, 1 Hz), 7.43-7.62 (m, 2H),7.64-7.69 (m, 2H), 7.74-7.79 (m, 2H), 8.56 (dd, 1H, J=5, 1 Hz); ¹³C NMR(CDCl₃) δ 21.3, 24.0, 29.1, 39.1, 49.2, 52.0, 61.0, 110.9, 118.7, 121.6,122.1, 123.2, 126.1, 132.0, 132.8, 133.9, 134.5, 137.2, 146.7, 156.3,157.5, 167.8. ES-MS m/z 478 (M+H). Anal. Calcd. forC₂₉H₂₇N₅O₂.0.2CH₂Cl₂.0.3H₂O: C, 70.15; H, 5.64; N, 14.01. Found: C,70.40; H, 5.73; N, 13.90.

Example 76

COMPOUND 76: Preparation of(Z)-N¹-(1H-Benzimidazol-2-ylmethyl)-N¹-5,6,7,8-tetrahydro-quinolin-8-yl-but-2-ene-1,4-diamine(hydrochloride salt)

(Z)-4-chloro-2-butenylamine hydrochloride (3.88 g, 27.3 mmol), water (1mL) and diisopropylethylamine (9.6 mL, 55.1 mmol) were dissolved intetrahydrofuran (140 mL) and stirred for 5 min. under nitrogen.Di-tert-butyl dicarbonate (15.31 g, 70.1 mmol) was added and the mixturewas stirred for an additional 4 h at 25° C. The mixture was concentratedand the residue dissolved in methylene chloride (100 mL) and washed withsaturated sodium bicarbonate (80 mL). The aqueous layer was extractedwith methylene chloride (2×50 mL). The combined organic layers weredried (MgSO₄) and concentrated to afford a brown oil which solidified onstanding. Purification by column chromatography on silica gel afforded6.4 g of a mixture of the desired product and di-tert-butyl dicarbonate.Recrystallization from hot hexanes afforded(4-chloro-but-2-enyl)-carbamic acid tert-butyl ester (3.27 g, 50%) aswhite crystals. ¹H NMR (CDCl₃) δ 1.45 (s, 9H), 3.83 (t, 2H, J=6.2 Hz),4.12 (d, 2H, J=7.4 Hz), 4.58 (bs, 1H), 5.58-5.68 (m, 1H), 5.71-5.81 (m,1H).

(4-Chloro-but-2-enyl)-carbamic acid tert-butyl ester (1.81 g, 7.47mmol), potassium iodide (59 mg, 0.36 mmol) and diisopropylethylamine(1.80 mL, 10.3 mmol) were added to a solution of2-[(5,6,7,8-tetrahydroquinolin-8-ylamino)-methyl]-benzimidazole-1-carboxylicacid tert-butyl ester (2.57 g, 6.79 mmol)) in acetonitrile (70 mL) andwarmed to 60° C. and stirred for 17 h under nitrogen. The solvent wasremoved in vacuo. The residue was dissolved in methylene chloride (100mL) and washed with brine (100 mL). The aqueous layer was extracted withmethylene chloride (2×150 mL). The combined organic layers were dried(Na₂SO₄) and concentrated. The crude mixture was purified by columnchromatography on silica gel (150 g) to afford2-{[(S)-((Z)-4-tert-butoxycarbonylamino-but-2-enyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (5.99 g, 88%) as a white foamy solid. ¹H NMR(CDCl₃) δ 1.43 (s, 9H), 1.72 (s, 9H), 1.95-2.08 (m, 4H), 2.09-2.20 (m,1H), 2.61 (d, 1H, J=16.2 Hz), 3.28 (dd, 1H, J=14.1, 5.4 Hz), 3.62 (dd,1H, J=13.7, 7.2 Hz), 3.69-3.85 (m, 2H), 4.29 (dd, 1H, J=9.2, 6.6 Hz),4.42 (d, 1H, J=14.9 Hz), 4.48 (d, 1H, J=14.9 Hz), 5.43-5.63 (m, 2H),6.19 (s, 1H), 6.87 (dd, 1H, J=7.5, 4.8 Hz), 7.17 (d, 1H, J=7.7 Hz),7.23-7.28 (m, 1H), 7.65-7.71 (m, 1H), 7.75-7.80 (m, 1H), 8.34 (d, 1H,J=4.4 Hz).

2-{[(S)-((Z)-4-tert-Butoxycarbonylamino-but-2-enyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester was dissolved in acetic acid (15 mL) and hydrogenchloride gas was bubbled through the solution for 10 min. The mixturewas stirred for an additional 60 min. then diluted with acetic acid (15mL). The acetic acid solution was added dropwise, over to a flaskcontaining of diethyl ether (600 mL), stirred rapidly, where a whitefluffy precipitate formed. The ether mixture was allowed to settle anddecanted. The slurry was washed with ether (3×500 mL) and then theprecipitate was collected on a glass frit and rinsed thoroughly withether. The frit was placed into a vacuum oven (40° C.) for 18 h toafford COMPOUND 76 as a light pink solid (2.20 g, 72%). ¹H NMR (D₂O) δ1.75-1.88 (m, 1H), 1.98-2.11 (m, 1H), 2.17-2.22 (m, 1H), 2.37-2.42 (m,1H), 3.00 (dd, 2H, J=7.8, 3.9 Hz), 3.25 (dd, 1H, J=14.7, 4.4 Hz),3.58-3.65 (m, 3H), 4.4.32 (d, 1H, J=16.5 Hz, 4.46-4.55 (m, 2H),5.43-5.53 (m, 1H), 5.77-5.86 (m, 1H), 7.55-7.62 (m, 2H), 7.74-7.81 (m,2H), 7.84 (dd, 1H, J=7.9, 5.9 Hz), 8.33 (d, 1H, J=7.8 Hz), 8.62 (d, 1H,J=5.4 Hz); ¹³C NMR (D₂O) 20.35, 20.47, 27.61, 36.45, 48.00, 48.67,60.52, 114.31 (2C), 124.75, 125.91, 126.81 (2C), 131.27, 132.58, 139.49,140.64, 147.98, 150.92, 151.47. ES-MS m/z 348 (M+H). Anal. Calcd. forC₂₁H₂₅N₅.3.1HCl.2.5H₂O.0.3Et₂O: C, 50.70; H, 6.88; N, 13.32; Cl, 20.90.Found C, 50.81; H, 6.89; N, 13.45; Cl, 20.80.

The enantiomeric purity of COMPOUND 76 was determined to be 98% bychiral HPLC using the following conditions: Instrument: Hewlett Packard1100 HPLC (VWD2); Column: ChiralPak AD, 4.6 cm×25 cm; Mobile Phases:A=90:10 hexanes/reagent alcohol with 0.1% DEA, B=reagent alcohol;Isocratic: 90% A, 10% B; Total Run Time: 40 min; Flow Rate: 0.5 mL/min;Temperature: 40° C.; Detector: UV @ 270 nm; Injection volume: 10 μL.

Retention time of the S enantiomer=21.4 min.

Retention time of the R enantiomer=14.3 min.

Example 77

COMPOUND 77: Preparation ofN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-(E)-but-2-ene-1,4-diamine

2-{[[(Z)-4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-but-2-enyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (prepared as described for COMPOUND 75) (200 mg,0.35 mmol) was taken up in EtOH (3 mL) and hydrazine monohydrate (0.5mL, 10 mmol) was added. The resulting mixture was heated to reflux for18 h, at which point saturated aqueous sodium bicarbonate (15 mL) wasadded, and the resulting mixture was extracted with CH₂Cl₂ (3×20 mL)then the combined organic extracts were dried (MgSO₄), and concentratedin vacuo. Purification of the crude material thus obtained by radialchromatography (silica gel, 1 mm plate, 50:1:1 CH₂Cl₂—MeOH—NH₄OH)afforded 53 mg (44%) of COMPOUND 77 as a white solid. ¹H NMR (CDCl₃) δ1.47-1.71 (m, 3H), 1.89-2.08 (m, 2H), 2.18-2.20 (m, 1H), 2.74-2.83 (m,2H), 3.13 (d, 2H, J=6 Hz), 3.25-3.27 (m, 2H), 4.06-4.10 (m, 3H), 5.46(dt, 1H, J=15, 6 Hz), 5.71 (dt, 1H, J=15, 6 Hz), 7.12-7.21 (m, 3H), 7.41(d, 1H, J=8 Hz), 7.50-7.58 (m, 2H), 8.60 (dd, 1H, J=5, 1 Hz); ¹³C NMR(CDCl₃) δ 21.3, 23.6, 29.2, 43.1, 48.8, 52.5, 61.3, 114.3, 121.5, 122.1,128.5, 133.4, 134.6, 137.3, 146.7, 156.4, 157.5. ES-MS m/z 348 (M+H).Anal. Calcd. for C₂₁H₂₅N₅.0.2CH₂Cl₂.0.9CH₄O: C, 67.49; H, 7.43; N,17.81. Found: C, 67.59; H, 7.31; N, 17.46.

Example 78

COMPOUND 78: Preparation ofN¹-(1H-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-but-2-yne-1,4-diaminePreparation of (4-chlorobut-2-ynyl)carbamic acid tert-butyl ester

To a stirred mixture of 1-amino-4-chloro-2-butyne hydrochloride (1.12 g,8.01 mmol) and Boc₂O (2.12 g, 9.71 mmol) in a solution of THF (40 mL)and H₂O (15 drops) was added DIPEA (3.1 mL, 17.8 mmol). The resultantsolution was stirred at room temperature for 4.5 hours. Saturatedaqueous NaHCO₃ (20 mL) was added, the layers were separated and theaqueous solution was extracted with Et₂O (25 mL×2). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification by flash column chromatography on silica gel(hexane/EtOAc, 7:3) gave the Boc-protected amine as an off-white solid(1.38 g, 6.79 mmol, 85%). ¹H NMR (CDCl₃) δ 1.44 (s, 9H), 3.97 (d, 2H,J=4.5 Hz), 4.13 (t, 2H, J=2.1 Hz), 4.74 (br. s, 1H).

Preparation of2-{[(4-tert-butoxycarbonylamino-2-butynyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester

A solution of the chloride from above (182 mg, 0.89 mmol),(1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(285 mg, 0.75 mmol), DIPEA (0.20 mL, 1.2 mmol) and catalytic KI (8 mg,0.05 mmol) in CH₃CN was heated at 60° C. for 17 hours. Saturated aqueousNaHCO₃ (10 mL) was added and the mixture was extracted with CH₂Cl₂ (25mL×3). The organic solution was dried (MgSO₄), filtered and evaporatedunder reduced pressure. Purification by flash column chromatography onsilica (CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1) gave the tertiary amine as a palebrown foam (374 mg, 0.69 mmol, 91%). ¹H NMR (CDCl₃) δ 1.43 (s, 9H), 1.67(s, 9H), 1.97-2.14 (m, 4H), 2.61-2.73 (m, 1H), 2.75-2.88 (m, 1H),3.61-3.80 (m, 4H), 4.31 (dd, 1H, J=7.8, 5.6 Hz), 4.45(d, 1H, J=15.9 Hz),4.54 (d, 1H, J=15.9 Hz), 4.63 (br. s, 1H), 7.01 (dd, 1H, J=7.5, 4.8 Hz),7.27-7.34 (m, 3H), 7.72 (dd, 1H, J=6.0, 3.0 Hz), 7.83 (dd, 1H, J=6.0,3.3 Hz), 8.39 (d, 1H, J=3.3 Hz).

Preparation of COMPOUND 78:

The di-Boc protected amine (365 mg, 0.67 mmol) was stirred in TFA (6 mL)at room temperature for 1.5 hours. Saturated aqueous NaHCO₃ (approx. 100mL) was added until the mixture was neutral and the aqueous solution wasextracted with CH₂Cl₂ (50 mL×3). The organic solution was dried(Na₂SO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,19:1:0.1) gave COMPOUND 78 as a beige foam (90.4 mg, 0.26 mmol, 39%). ¹HNMR (CDCl₃) δ 1.65-1.79 (m, 1H), 1.94-2.14 (m, 2H), 2.16-2.28 (m, 1H),2.69-2.81 (m, 1H), 2.81-2.95 (m, 1H), 3.21 (s, 2H), 3.54 (d, 2H, J=2.1Hz), 4.04 (d, 1H, J=16.2 Hz), 4.15 (d, 1H, J=16.2 Hz), 7.14-7.23 (m,3H), 7.45 (d, 1H, J=7.5 Hz), 7.54-7.64 (m, 2H), 8.58 (d, 1H, J=4.3 Hz).¹³C NMR (CDCl₃) δ 21.1, 24.6, 29.3, 31.9, 41.0, 49.9, 61.6, 79.2, 85.8,122.1, 122.8, 135.0, 137.9, 147.0, 155.5, 157.4. ES-MS m/z 346 (M+H).Anal. Calcd. for C₂₁H₂₃N₅.0.2CH₂Cl₂.0.1C₄H₁₀O: C, 70.15; H, 6.65; N,18.94. Found: C, 69.97; H, 6.85; N, 18.96.

Example 79

COMPOUND 79: 3-Aminomethyl-N′-(1H-benzimidazol-2-ylmethyl)-N′-(5.6.7.8-tetrahydro-quinolin-8-yl)-but-2-ene-1,4-diamine(hydrobromide salt) Preparation of(3-tert-Butoxycarbonylamino-2-oxo-propyl)-carbamic acid tert-butyl ester

To a suspension of 1,3-diamino-2-hydroxypropane (2.43 g, 0.027 mol) inTHF/H₂O (15:1, 80 mL) was added di-tert-butyl dicarbonate (11.77 g,0.054 mol) and the reaction stirred for 2.5 h then concentrated invacuo.

To a solution of oxalyl chloride in CH₂Cl₂ (2.0 M, 7.7 mL, 15.4 mmol) at−78° C. was added a solution of DMSO (1.7 ml, 24.0 mmol) in CH₂Cl₂ (12mL) and the mixture allowed to stir for 30 min. at −78° C., after whichthe crude alcohol from above (2.86 g) in CH₂Cl₂ (10 ml) was addeddropwise. Stirring was continued for 15 min. and then Et₃N (5.0 ml, 35.9mmol) was added dropwise. The cooling bath was removed, stirring wascontinued for 1.5 h, and the mixture was diluted with CH₂Cl₂ (20 ml) andwater (30 mL). The aqueous layer was extracted with CH₂Cl₂ (20 ml) andthe combined organic extracts were washed with brine (30 mL), dried overNa₂SO₄ and concentrated. Evaporation of the solvent and purification ofthe residue by flash chromatography on silica gel, using 40% ethylacetate in CH₂Cl₂, gave the title compound (350 mg, 16% over 2 steps) asa beige solid. ¹H NMR (CDCl₃) δ 1.42 (s, 18H), 4.03 (br d, 4H, J=6 Hz),5.26 (br s, 2H).

Preparation of(4-tert-butoxycarbonylamino-3-(tert-butoxycarbonylamino-methyl)-but-2-enoicacid ethyl ester

To a solution of (3-tert-butoxycarbonylamino-2-oxo-propyl)-carbamic acidtert-butyl ester (310 mg, 1.08 mmol) in benzene (20 mL) was added(carbethoxymethylene)-triphenyl phosphorane (825 mg, 2.37 mmol) and thereaction mixture was stirred at 45° C. overnight. Then the mixture wascooled to room temperature and the solvent concentrated down.Purification by radical chromatography on silica gel (2 mm plate, usingCH₂Cl₂) afforded the desired compound as a yellow oil (290 mg, 75%). ¹HNMR (CDCl₃) δ 1.26 (t, 3H, J=9.0 Hz), 1.42 (s, 18H), 3.87 (d, 2H, J=6.0Hz), 4.09 (d, 2H, J=6.0 Hz), 4.15 (q, 2H, J=9.0 Hz), 5.34 (br s, 1H),5.85 (s, 1H), 7.34 (s, 1H).

Preparation of[2-(tert-butoxycarbonylaminomethyl)-4-hydroxy-but-2-enyl]-carbamic acidtert-butyl ester

To a solution of the above ester (290 mg, 0.81 mmol) in THF (10 mL) wasadded DIBAL (1.0 M in CH₂Cl₂) (2.4 mL, 2.42 mmol) at −78° C. Thetemperature was increased to room temperature after 40 minutes. After 1hour, the reaction was quenched with Rochelle's salt (10 mL) and wasstirred overnight. Then it was extracted with CH₂Cl₂ (3×10 mL). Thecombined organic extracts were dried (Na2SO₄), filtered, concentrated,and dried in vacuo to afford a yellow oil. Purification by flash columnchromatography on silica gel using 50% hexanes/ethyl acetate affordedthe desired product as a pale yellow oil (210 mg, 83%). ¹H NMR (CDCl₃) δ1.42 (s, 10H), 1.85 (br t, 1H), 3.89 (d, 4H, J=9.0 Hz), 4.15 (t, 2H,J=7.5 Hz), 4.75 (br t, 1H), 5.55 (br s, 1H), 5.78 (t, 1H, J=7.5 Hz).

Preparation of2-{[[4-tert-butoxycarbonylamino-3-(tert-butoxycarbonylamino-methyl)-but-2-enyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester

To a solution of the above alcohol (107 mg, 0.34 mmol) and triethylamine(70 μL, 0.41 mmol) in CH₂Cl₂ was added methanesulfonyl chloride (30 μL,0.41 mmol) at 0° C. After 20 minutes at that temperature, the reactionmixture was quenched with saturated NH₄Cl (10 mL). The organic layer waswashed with saturated NH₄Cl (2×10 mL), dried (Na₂SO₄), filtered,concentrated, and dried in vacuo to afford a yellow oil (150 mg). Thiswas used without further purification. ¹H NMR (CDCl₃) δ 1.43 (s, 18H),3.02 (s, 3H), 3.76 (t, 4H, J=6.0 Hz), 4.89 (d, 2H, J=6.0 Hz), 4.90 (brs, 1H), 4.99 (br s, 1H), 5.64 (t, 1H, J=6.0 Hz).

The above mesylate (150 mg, 0.43 mmol),2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzimidazole-1-carboxylicacid tert-butyl ester (195 mg, 0.52 mmol), N,N-diisopropylethylamine (90mL, 0.52 mmol), and potassium iodide (7 mg, 0.04 mmol) in CH₃CN (10 mL)was stirred at 40° C. for three days. Then the solvent was concentrateddown and the residue was dissolved in CH₂Cl₂ (15 mL). The organic layerwas extracted with saturated NaHCO₃ (3×15 mL), dried (MgSO₄), filtered,concentrated, and dried in vacuo to afford a yellow oil. Purification byfour attempts at radial chromatography on silica gel (2 mm plate, usingCH₃OH/NH₄OH/CH₂Cl₂ (0:1:99→4:1:95); 1 mm plate, using CH₃OH/NH₄OH/CH₂Cl₂(0:1:99→2:1:97); 1 mm plate, using ethyl acetate; 1 mm plate, usingCH₃OH/NH₄OH/CH₂Cl₂ (1:1:100)) afforded the desired compound as a whilefoam (39 mg,13%). ¹H NMR (CDCl₃) δ 1.38 (s, 9H), 1.43 (s, 9H), 1.70 (s,9H), 2.04-2.11 (m, 3H), 2.56 (d, 1H, J=16.2 Hz), 2.77 (br t, 1H), 3.22(dd, 1H, J=13.7, 6.2 Hz), 3.39 (dd, 1H, J=15.6, 5.4 Hz), 3.49-3.58 (m,2H), 3.76 (dd, 1H, J=14.1, 8.1 Hz), 3.96 (dd, 1H, J=14.1, 4.2 Hz), 4.22(t, 1H, J=8.1 Hz), 4.39 (ABq, 2H, J=38.4, 14.4 Hz), 5.20 (br m, 1H),5.47 (br m, 1H), 6.72 (dd, 1H, J=7.5, 4.8 Hz), 7.04 (d, 1H, J=7.2 Hz),7.20-7.25 (m, 3H), 7.54-7.62 (m, 2H), 7.69-7.72 (m, 1H), 8.25 (d, 1H,J=3.9 Hz).

Preparation of3-aminomethyl-N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-but-2-ene-1,4-diamine(hydrobromide salt)

To a solution of the above diamine (39 mg, 0.06 mmol) in acetic acid (1mL) was added a hydrobromic acid saturated acetic acid (0.5 mL) and thereaction mixture was stirred for 20 minutes. Then diethyl ether wasadded until the precipitation of COMPOUND 79 was afforded as a pinksolid (20 mg, 30%). ¹H NMR (D₂O) δ 1.76-1.84 (m, 1H), 2.16-2.21 (m, 1H),2.37-2.41 (m, 1H), 2.98 (br d, 2H, J=5.1 Hz), 3.41 (dm, 1H, J=15.0 Hz),3.68-3.70 (m, 3H), 3.76-3.85 (m, 2H), 4.26-4.46 (m, 3H), 6.23 (dd, 1H,J=10.8, 4.2 Hz), 7.56-7.60 (m, 2H), 7.73-7.84 (m, 3H), 8.30 (d, 1H,J=7.5 Hz), 8.59 (d, 1H), J=6.0 Hz). ¹³C NMR (D₂O) δ 20.22, 20.30, 27.59,37.12, 42.32, 46.68, 48.91, 59.19, 114.28, 126.03, 127.04, 128.73,131.00, 136.26, 139.60, 140.88, 148.14, 150.51. ES-MS m/z 399 [M+H]⁺,399 [M+Na]⁺. Anal. Calcd. for C₂₂H⁻²⁸N₆.4.2HBr.2.2H₂O.0.6C₄H₁₀O: C,36.61; H, 5.36; N, 10.50; Br, 41.93. Found: C, 36.68; H, 5.08; N, 10.48;Br, 41.87.

Example 80

COMPOUND 80: Preparation of(E)-2-aminomethyl-4-[(1H-benzimidazol-2-yl-methyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-but-2-en-1-ol

To a solution of 3-amino-1,2 propanediol (7.75 g, 0.085 mmol) in THF(430 mL) was added water (20 mL) followed by tert-butyl dicarbonate(19.60 g, 0.0898 mmol) in one portion. The solution was stirred at roomtemperature for 23 hours. The solvent was removed under reduced pressureand the residue was dissolved in EtOAc (100 mL) and saturated sodiumcarbonate (100 mL). The phases were separated and the aqueous phase wasextracted with ethyl acetate (3×75 mL). The combined organic extractswere dried over sodium sulfate, filtered, concentrated to give(1,2-dihydroxy-ethyl)-carbamic acid tert-butyl ester as a crude whitesolid (15 g, 92%).

To a solution of crude from above (494 mg, 2.6 mmol) in CH₂Cl₂ (13 mL)was added imidazole (236 mg, 3.5 mmol) followed by TBDMS—Cl (410 mg, 2.7mmol) and the reaction was stirred at room temperature overnight. Thereaction mixture was diluted with CH₂Cl₂ (40 mL) and saturated aqueoussodium bicarbonate (40 mL). The phases were separated and the aqueouslayer was extracted with CH₂Cl₂ (3×30 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated. Purificationof the crude material by column chromatography (15g silica, 8:1hexanes/EtOAc) gave[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-ethyl]-carbamic acidtert-butyl ester as a colorless oil (555 mg, 70%). ¹H NMR (CDCl₃) δ:4.96 (broad s, 1H), 3.74-3.71 (m, 1H), 3.67-3.62 (m, 1H), 3.56-3.50 (m,1H), 1.44 (s, 9H), 0.90 (s, 9H), 0.07 (s, 6H).

To a solution of the above material (555 mg, 1.81 mmol) in CH₂Cl₂ (9 mL)was added NMO (324 mg, 2.77 mmol), followed by 3 Å molecular sieves (960mg) and TPAP (62 mg, 0.18 mmol). The green-black solution was stirred atroom temperature for 2 hours. TLC (2:1 hexane/EtOAc-stained inninhydrin) monitored the reaction. The reaction mixture was filteredthrough a cake of silica gel and the cake was washed with ethyl acetate.The filtrate was concentrated to provide crude[2-(tert-butyl-dimethyl-silanyloxy)-acetyl]-carbamic acid tert-butylester as a yellow oil (458 mg, 83%).

Preparation of3-tert-butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-but-2-enoicacid ethyl ester

To the ketone from above (458 mg, 1.51 mmol) in benzene (8 mL) was added(carbethoxymethylene)triphenyl phosphorane (815 mg, 2.35 mmol). Thereaction mixture was heated to ˜40-45° C. and stirred at thistemperature overnight. The reaction mixture was then concentrated andthe residue purified by column chromatography (25 g silica, 25:1hexane/EtOAc) to give two yellow oils (cis/trans isomers) as majorproducts (430 mg total, 76%). ¹H NMR of trans-isomer (CDCl₃) δ: 6.06 (s,1H), 5.41 (broad s, 1H), 4.31 (s, 2H), 4.18 (q, 2H, J=7.5 Hz), 3.94 (d,2H, J=7.0 Hz), 1.42 (s, 9H), 1.30 (t, 3H, J=7.5 Hz), 0.92 (s, 9), 0.07(s, 6H). ¹H NMR of cis-isomer (CDCl₃) δ: 5.78 (s, 1H), 4.87 (s, 2H),4.14 (q, 2H, J=7.5 Hz), 4.00 (d, 2H, J=7.0 Hz), 1.45 (s, 9H), 1.27 (t,3H, J=7.5 Hz), 0.91 (s, 9H), 0.09 (s, 6H).

To a solution ofTrans-3-tert-butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-but-2-enoicacid ethyl ester (0.66 g, 1.8 mmol) in dichloromethane (18 mL) added asolution of DIBAL-H (8.8 mL, 1.0 M in CH₂Cl₂, 8.8 mmol) at 0° C. Thesolution was allowed to stir for 1 h while warming to room temperature.Saturated potassium sodium tartrate solution (20 mL) was then added andthe solution stirred for another hour. The phases were separated and theorganic phase dried (MgSO₄), filtered and concentrated under reducedpressure to give, after column chromatography (1:3 ethylacetate/hexane),trans-[2-(tert-butyl-dimethyl-silanyloxymethyl)-4-hydroxy-but-2-enyl]-carbamicacid tert-butyl ester (0.255 g, 39%).

Methanesulfonyl chloride (65 μL, 0.8 mmol) and triethylamine (0.15 mL,1.0 mmol) was added to a solution of the above alcohol (0.23 g, 0.7mmol) in dichloromethane (7.0 mL) at room temperature and stirred 0.5hours. This gave, after aqueous work up, the crude allylicmethanesulfonate (0.25 g, 80%) as a pale yellow crystalline solid.

Using general procedure D from above, the above methanesulfonate (0.25g, 0.7 mmol),(N-tert-butoxycarbonylbenzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(0.26 g, 0.70 mmol) and potassium iodide (6 mg, 35 μmol) were stirred at60° C. in acetonitrile (7.0 mL) and diisopropylethylamine (0.18 mL, 1.0mmol) ) for 16 hours to yield, after work-up and column chromatography(2.5:97.5 MeOH/CH₂Cl₂), the desired alkylated E-regioisomer (0.200 g,42%).

A solution of the above compound (0.20 g, 0.30 mmol) in THF (1.0 mL) wastreated with TBAF (0.6 mL, 1.0 M in THF, 0.6 mmol) for 0.5 hours. Thisgave, after column chromatography (1:99 MeOH/CH₂Cl₂), thedi-boc-protectedE-2-{[[3-(tert-butoxycarbonylaminomethyl)-4-hydroxy-but-2-enyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (60 mg, 38%). ¹H NMR (CDCl₃) δ 1.41 (s, 9H), 1.65(br, 1H), 1.69 (s, 9H), 2.11 (m, 3H), 2.60 (m, 1H), 2.77 (m, 1H), 3.27(m, 1H), 3.60 (m, 1H), 3.88 (m, 3H), 4.07 (m, 1H), 4.23 (m, 1H), 4.29(d, 1H, J=15.0 Hz), 4.46 (d, 1H, J=15.0 Hz), 5.50 (m, 1H), 6.74 (m, 1H),7.05 (d, 1H, J=6.0 Hz), 7.24 (m, 2H), 7.59 (m, 1H), 7.70 (m, 2H), 8.26(d, 1H, J=3.0 Hz).

The above material (60 mg, 0.11 mmol) was then dissolved in neat TFA (1mL) and stirred for 1 hour. CH₂Cl₂ (10 mL) and 15% aqueous NaOH wasadded until pH=13. The organic phase was separated and the aqueous phasewas extracted with CH₂Cl₂ (2×5 mL). The combined organic phases werethen dried (MgSO4), filtered, and concentrated under reduced pressure toprovide COMPOUND 80 free base as a pale yellow free flowing powder (14mg, 10%). ¹H NMR (CDCl₃) δ 1.66 (br, 1H), 1.85 (m, 1H), 2.00 (br, 1H),2.17 (br, 1H), 2.80 (m, 3H), 3.19 (m, 1H), 3.30 (m, 1H), 3.36 (s, 2H),3.90 (d, 1H, J=15.0 Hz), 4.01 (d, 1H, J=18.0 Hz), 4.10 (br, 3H), 5.64(m, 1H), 7.09 (m, 1H), 7.15 (m, 2H), 7.40 (d, 1H, J=9.0 Hz), 7.54 (br,2H), 8.49 (d, 1H, J=3.0 Hz); ¹³C NMR (CDCl₃) δ 21.46, 23.21, 29.47,39.86, 47.47, 49.46, 61.34, 67.08, 115.11 (3C), 122.165 (2C), 122.62,126.31 (2C), 135.25, 137.97, 142.19, 147.02, 155.11, 157.26. ES-MS m/z378 (M+H). Anal. Calcd. for C₂₂H₂₇N₅O.0.7CH₂Cl₂: C, 62.40; H, 6.55; N,16.03. Found: C, 62.70; H, 6.70; N, 15.97.

Example 81

COMPOUND 81: Preparation of(Z)-2-aminomethyl-4-[(1H-benzimidazol-2-yl-methyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-but-2-en-1-ol

To a solution ofcis-3-tert-butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-but-2-enoicacid ethyl ester (0.49 g, 1.3 mmol) in dichloromethane (13 mL) was addeda solution of DIBAL-H (6.5 mL, 1.0 M in CH₂Cl₂, 6.5 mmol) at 0° C. Thesolution was allowed to stir for 1 h while warming to room temperature.Saturated potassium sodium tartrate solution (15 mL) was then added andthe solution stirred for another hour. The phases were separated and theorganic phase dried (MgSO₄), filtered and concentrated to give the crudecis-[2-(tert-butyl-dimethyl-silanyloxymethyl)-4-hydroxy-but-2-enyl]-carbamicacid tert-butyl ester (0.33 g, 77%).

Methanesulfonyl chloride (39 μL, 0.42 mmol) and triethylamine (0.090 mL,0.63 mmol) was added to a solution of the above alcohol (0.14 g, 0.42mmol) in dichloromethane (4.2 mL) at room temperature and stirred 0.5hours. This gave, after aqueous work up, the crude allylicmethanesulfonate (0.14 g) which was used immmediately in the nextreaction.

Using the general procedure for N-alkylation, the methanesulfonate (0.14g, 0.42 mmol),(N-tert-butoxycarbonylbenzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(0.16 g, 0.42 mmol) and potassium iodide (3 mg, 21 μmol) were stirred at60° C. in acetonitrile (4.2 mL) and diisopropylethylamine (0.11 mL, 0.63mmol) ) for 16 hours to yield, after work-up and column chromatography(1:99 MeOH/CH₂Cl₂), the desired alkylated Z-regioisomer (0.100 g, 34%).

A solution of the above compound (0.10 g, 0.16 mmol) in THF (2 mL) and3N HCl (2 mL) was stirred for 1.5 hours. The solution was then cooled to0° C. and 15% aqueous sodium hydroxide was added until the pH=12. Theaqueous phase was then extracted with CH₂Cl₂ (3×15 mL) and the combinedorganic phases were dried (MgSO₄), filtered and concentrated underreduced pressure. This gave, after radial chromatography (8:2.5:89.5MeOH/NH₄OH/CH₂Cl₂),Z-{4-[(1H-benzimidazol-2-yl-methyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-2-hydroxymethyl-but-2-enyl}-carbamicacid tert-butyl ester (35 mg, 58%). ¹H NMR (CDCl₃) δ 1.40 (s, 9H), 1.77(br, 1H), 1.97 (m, 1H), 2.10 (m, 3H), 2.80 (m, 2H), 3.27 (m, 2H), 3.64(br, 2H), 3.72 (d, 1H, J=15.0 Hz), 3.92 (d, 1H, J=15.0 Hz), 4.02 (s,2H), 4.12 (m, 1H), 4.58 (m, NH), 7.18 (m, 3H), 7.50 (m, 2H), 7.68 (br,1H), 8.52 (d, 1H, J=3.0 Hz).

The above compound (35 mg, 0.07 mmol) was then dissolved in neat TFA (1mL) and stirred for 1 hour. CH₂Cl₂ (10 mL) and 15% aqueous NaOH wasadded until pH=12. The organic phase was separated and the aqueous phasewas extracted with CH₂Cl₂ (2×5 mL). The combined organic phases weredried (MgSO4), filtered, and concentrated under reduced pressure. Thisafforded, after radial chromatography (8:2.5:89.5 MeOH/NH₄OH/CH₂Cl₂),COMPOUND 81 free base as a pale yellow free flowing powder (18 mg, 68%).¹H NMR (CDCl₃) δ 1.75 (br, 1H), 1.94 (m, 1H), 2.08 (br, 2H), 2.85 (m,3H), 3.30 (m, 4H), 3.78 (d, 1H, J=14.4 Hz), 3.95 (d, 1H, J=15.6 Hz),4.11 (d 2H), 4.15 (m, 1H), 5.48 (m, 1H), 7.19 (m, 3H), 7.46 (d, 1H,J=7.2 Hz), 7.58 (br, 2H), 8.53 (d, 1H, J=3.3 Hz); ¹³C NMR (CDCl₃) δ20.88, 23.54, 29.20, 47.22, 47.74, 49.28, 59.50, 61.77, 115.24 (3C),122.42 (2C), 122.82, 125.40 (2C), 135.27, 138.23, 143.73, 146.88,155.01, 157.26. ES-MS m/z 378 (M+H). Anal. Calcd. forC₂₂H₂₇N₅O.0.7CH₂Cl₂.0.2C₆H₁₂: C, 63.26; H, 6.84; N, 15.43. Found: C,63.36; H, 6.79; N, 15.59.

Example 82

COMPOUND 82: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-cyclohexane-trans-1,2-diamine(hydrobromide salt) Preparation ofN-(2-nitrobenzenesulfonyl)-7-azabicyclo[4.1.0]heptane(N-(2-nitrobenzenesulfonyl)-1,2-cyclohexeneaziridine)

A solution of trans-2-aminocyclohexanol hydrochloride (1.185 g, 7.81mmol) and 2-nitrobenzenesulfonyl chloride (1.73 g, 7.81 mmol) in CH₂Cl₂(20 mL) was cooled in an ice bath under a nitrogen atmosphere while Et₃N(2.40 mL, 17.2 mmol) was added. The mixture was heated at reflux for 35minutes, then concentrated in vacuo. Water (100 mL) was added to theresidue, and the mixture was extracted with EtOAc (100 mL). The organicextract was washed with brine (2×30 mL), then dried (MgSO₄), filteredand concentrated in vacuo to give a green foam (2.32 g).

A solution of the foam from above and Et₃N (1.3 mL, 9.3 mmol) in CH₂Cl₂(15 mL) was stirred at −78° C. under argon while methanesulfonylchloride (0.66 mL, 8.5 mmol) was added. The mixture was stirred at −78°C. for 10 minutes, then the cold bath was removed and stirring wascontinued at room temperature for 30 minutes and the solution was thenconcentrated in vacuo. Water (30 mL) and saturated NaHCO₃(aq) (30 mL)were added to the residue, and the mixture was extracted with EtOAc(1×50 mL, 3×20 mL). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo to give the crude mesylate as a light yellow solid(2.65 g).

The crude mesylate (2.65 g, 7.0 mmol) was stirred as a suspension intoluene (30 mL) at room temperature while a solution of 85% KOH (2.01 g,35.9 mmol) in H₂O (12 mL) was added. The mixture was stirred for 40minutes then diluted with EtOAc (50 mL) and brine (40 mL). The aqueousphase was separated and washed with EtOAc (1×40 mL) then dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (25% EtOAc/hexanes) to give the desiredaziridine as colorless crystals (1.54 g, 71% over 3 steps). ¹H NMR(CDCl₃) δ 1.23-1.30 (m, 2H), 1.35-1.42 (m, 2H), 1.84-1.93 (m, 4H), 3.22(dd, 2H, J=6, 1 Hz), 7.72-7.76 (m, 3H), 8.18-8.20 (m, 1H).

A solution of N-(2-nitrobenzenesulfonyl)-1,2-cyclohexeneaziridine fromabove (341 mg, 1.21 mmol),(1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(434 mg, 1.15 mmol) and Et₃N (0.16 mL, 1.15 mmol) in THF (5 mL) washeated at 60° C. under nitrogen atmosphere for 2.5 days. The solutionwas then cooled, concentrated and diluted with CH₂Cl₂ (40 mL) andsaturated aqueous NaHCO₃ (40 mL). The aqueous phase was extracted withCH₂Cl₂ (2×20 mL). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH, 98:2 then 96:4) to give thedesired alkylated product as a yellow foam (411 mg, 54%).

The foam from above (271 mg, 0.41 mmol) oil was dissolved in CH₂Cl₂/TFA(1:1, 2 mL) and the mixture stirred overnight. The reaction was thenconcentrated and diluted with CH₂Cl₂ (30 mL) and 1 N NaOH (30 mL). Theaqueous layer was washed with CH₂Cl₂ (2×10 mL) and the combined organicextracts were dried (Na₂SO₄), filtered and concentrated to afford theBoc-deprotected material as a yellow foam (159 mg, 69%).

Deprotection of the 2-nitrobenzenesulfonamide(nosyl) group: To a stirredsolution of the nosyl-protected adduct from above (159 mg, 0.28 mmol) indry CH₃CN (5 mL) was added benzenethiol (0.175 mL, 1.71 mmol) andpowdered potassium carbonate (240 mg, 1.74 mmol) and the mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo and partitioned between CH₂Cl₂ (15 mL) and water(15 mL). The aqueous layer was separated and extracted with CH₂Cl₂ (2×10mL) and the combined organic phases were dried (Na₂SO₄), filtered andevaporated in vacuo to give the crude product as a yellow oil.Purification by column chromatography on basic alumina (CH₂Cl₂/MeOH,100:0 followed by 95:5) afforded the desired amine (85 mg, 80%) as ayellow foam.

Using General Procedure D: Conversion of the foam from above (34 mg,0.091 mmol) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave COMPOUND 82 (38 mg, 65%) asa white solid. ¹H NMR (D₂O) δ 1.36-1.46 (m, 2H), 1.59-1.91 (m, 5H),2.22-2.32 (m, 3H), 2.35-2.45 (m, 2H), 2.81-2.84 (m, 2H), 3.21-3.28 (m,1H), 3.44-3.56 (m, 1H), 4.33 (d, 1H, J=15.9 Hz), 4.42 (d, 1H, J=15.9Hz), 4.65 (t, 1H, J=8.4 Hz), 7.23 (dd, 1H, J=7.5, 6 Hz), 7.51 (dd, 2H,J=6.3, 3.3 Hz), 7.59 (dd, 2H, J=6.3, 3.3 Hz), 7.86 (d, 1H, J=8.1 Hz),8.11 (d, 1H, J=5.5 Hz); ¹³C NMR (D₂O) δ 19.35, 22.02, 22.46, 23.56,26.46, 27.94, 29.94, 37.81, 50.82, 61.34, 66.88, 112.92, 123.83, 126.14,129.54, 138.38, 139.34, 146.03, 148.26, 148.34. ES-MS m/z 376 (M+H).Anal. Calcd. for C₂₃H₂₉N₅.2.9HBr.1.8H₂O: C, 42.99; H, 5.57; N, 10.90;Br, 36.06. Found: C, 43.29; H, 5.55; N, 10.60; Br, 35.67.

Example 83

COMPOUND 83: Preparation ofN-(1H-benzimidazol-2-ylmethyl)-N-(5,6.7,8-tetrahydro-quinolin-8-yl)-cyclohexane-1,3-diamine(hydrobromide salt) Preparation ofN-tert-butoxycarbonyl-1,3-cyclohexanediamine (Smith, J.; Liras, J. L.;Schneider, S. E.; Anslyn, E J. Org. Chem. 1996, 61, 8811-8818)

To a solution of 1,3-cyclohexanediamine (cis and trans) (1.00 g, 8.76mmol) in CHCl₃ (20 mL) was added a solution of di-tert-butyl dicarbonate(0.95 g, 4.35 mmol) in CHCl₃ (15 mL) via syringe pump over a period of 3hours. The resultant white suspension was stirred at room temperatureovernight then concentrated in vacuo and purified by columnchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 90:8:2) to afford thetitle compound (0.66 g, 35% based on starting diamine) as a clear oil.

Following General Procedure B: To a stirred solution of6,7-dihydro-5H-quinolin-8-one (444 mg, 3.00 mmol) andN-tert-butoxycarbonyl-1,3-cyclohexanediamine (660 mg, 3.08 mmol) in dryTHF (5 mL) was added AcOH (0.4 mL) and NaBH(OAc)₃ (822 mg, 3.88 mmol)and the mixture stirred overnight at room temperature. Purification bycolumn chromatography on silica gel (CH₂Cl₂/MeOH, 96:4) afforded thedesired amine (370 mg, 60%) as a mixture of inseparable diastereomers.

Following the general procedure for N-alkylation: To a stirred solutionof the yellow foam from above (370 mg, 1.07 mmol) in CH₃CN (5 mL) wasadded N,N-diisopropylethylamine (0.35 mL, 2.01 mmol), KI (30 mg, 0.18mmol) and 1-(tert-butoxycarbonyl)-2-(chloromethyl)benzimidazole (343 mg,1.29 mmol). The mixture was stirred at 60° C. overnight. Purification ofthe resultant orange foam by column chromatography on silica gel(CH₂Cl₂/MeOH, 96:4 then 92:8) afforded the desired alkylated amine (430mg, 70%) as a mixture of diastereomers.

Using General Procedure D: Conversion of the foam from above (96 mg,0.17 mmol) to the hydrobromide salt with simultaneous removal of theN-tert-butoxycarbonyl protecting group followed by re-precipitation ofthe intermediate solid from methanol/ether gave COMPOUND 83 (96 mg, 88%)as an orange solid (mixture of diastereomers). ¹H NMR (D₂O) δ 1.27-1.64(m, 4H), 1.74-2.00 (m, 4H), 2.07-2.38 (m, 3H), 2.40-2.44 (m, 1H),2.84-2.90 (m, 1H), 2.98-3.01 (m, 2H), 3.15-3.20 (m, 1H), 4.43-4.62 (m,3H), 7.60 (dd, 2H, J=6, 3 Hz), 7.76 (dd, 2H, J=6, 3 Hz), 7.78-7.83 (m,1H), 8.28 (br d, 1H, J=7.8 Hz), 8.57-8.60 (m, 1H); ¹³C NMR (D₂O) δ19.58, 20.71, 22.37, 22.45, 24.23, 27.21, 27.51, 28.60, 29.16, 29.70,30.54, 31.08, 31.75, 34.35, 36.21, 43.65, 48.61, 49.79, 54.46, 58.57,58.70, 58.93, 114.23, 125.86, 127.05, 130.91, 139.16, 140.55, 148.03,151.18, 151.26, 151.83. ES-MS m/z 376 (M+H). Anal. Calcd. forC₂₃H₂₉N₅.3.0HBr.1.96H₂O: C, 42.34; H, 5.53; N, 10.73; Br, 36.74. Found:C, 42.27; H, 5.59; N, 10.37; Br, 37.04.

Example 85

COMPOUND 85: Preparation of(1H-benzimidazol-2-ylmethyl)-[2-(4-benzylamino-piperidin-1-yl)-ethyl]-(56,7,8-tetrahydroquinolin-8-yl)-amine (hydrobromide salt)

To a solution of N-Boc-piperidone (3.0 g, 15.1 mmol) in THF (76 mL) wasadded benzylamine (1.65 mL, 15.1 mmol), acetic acid (0.86 mL, 15.1 mmol)and sodium triacetoxyborohydride (4.8 g, 22.6 mmol). After stirring 2.5hours the reaction mixture was concentrated under reduced pressure andCH₂Cl₂ (50 mL) and saturated aqueous NaHCO₃ solution (50 mL) was added.The organic phase was separated, and the aqueous was extracted withCH₂Cl₂ (2×50 mL). The combined organic phases were then dried (MgSO₄),filtered, and concentrated under reduced pressure to afford4-benzylamino-piperidine-1-carboxylic acid tert-butyl ester (4.30 g,98%).

The crude material from above (4.30 g, 14.8 mmol) and2-nitrobenzenesulfonyl chloride (3.60 g, 16.3 mmol) were dissolved inCH₂Cl₂ (75 mL) and triethylamine (2.68 mL, 19.2 mmol) was added. Thesolution was stirred for 16 h and saturated aqueous NaHCO₃ solution (70mL) was added. The organic phase was separated, and the aqueousextracted with CH₂Cl₂ (50 mL). The combined organic phases were thendried (MgSO₄), filtered, and concentrated under reduced pressure. Thisgave, after column chromatography (CH₂Cl₂), the desired nosyl-protectedsubstrate (3.92 g, 56%).

A solution of the above material (3.92 g, 8.2 mmol) in 1:1 TFA/CH₂Cl₂(26 mL) was stirred for 0.5 h and then concentrated under reducedpressure. CH₂Cl₂ (50 mL), saturated aqueous NaHCO₃ solution (50 mL), and15% aqueous NaOH (10 mL) was added until pH=14. The organic phase wasseparated, and the aqueous was extracted with CH₂Cl₂ (30 mL). Thecombined organic phases were then dried (MgSO₄), filtered, andconcentrated under reduced pressure. This afforded the desiredunprotected cyclic amine (2.74 g, 89%).

To a solution of the cyclic amine (2.74 g, 7.3 mmol) in anhydrousacetonitrile (73 mL) was added 2-bromoethanol (0.52 mL, 7.3 mmol), andtriethylamine (1.25 mL, 8.7 mmol). The reaction was stirred at 50° C.for 16 hours, and saturated aqueous NaHCO₃ solution (50 mL) and ethylacetate (50 mL) was added. After separating the organic phase andwashing with brine (35 mL), the extracts were dried (MgSO₄), filteredand concentrated under reduced pressure. This gave, after columnchromatography (2:98 MeOH/CH₂Cl₂),N-benzyl-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-2-nitro-benzenesulfonamideas a colorless solid (1.62 g, 53%). ¹H NMR (CDCl₃) δ 1.62-1.71 (m, 4H),2.14 (dt, 2H, J=12.0, 3.0 Hz), 2.47 (t, 2H, J=6.0 Hz), 2.88 (br d, 2H,J=12.0 Hz), 3.53 (t, 2H, J=4.5 Hz), 3.92 (m, 1H), 4.54 (s, 2H), 7.21 (m,3H), 7.30 (m, 2H), 7.47 (m, 1H), 7.61 (d, 2H, J=4.5 Hz), 7.77 (d, 1H,J=9.0 Hz).

Methanesulfonyl chloride (100 μL, 1.2 mmol) and triethylamine (0.20 mL,1.4 mmol) was added to a solution of the above alcohol (0.40 g, 0.95mmol) in CH₂Cl₂ (3 mL) at 0° C. and then allowed to warm to roomtemperature over 20 minutes. This gave, after aqueous work up, thedesired crude methanesulfonate (0.53 g, quant) as a white solid whichwas used immediately in the next reaction.

Using the general procedure for N-alkylation, the crude methanesulfonate(0.47 g, 0.94 mmol) and(N-tert-butoxycarbonylbenzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(0.36 g, 0.94 mmol) was stirred at room temperature in acetonitrile (10mL) and diisopropylethylamine (0.25 mL, 1.4 mmol) for 16 hours. Thisyielded, after work-up and column chromatography (5:95 MeOH/CH₂Cl₂),2-{[{2-[4-(benzyl-2-nitrobenzenesulfonyl-amino)-piperidin-1-yl]-ethyl}-(5,6,7,8-tertahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester as a colorless flaky solid (0.25 g, 34%).

To a solution of the above material (0.25 g, 0.32 mmol) and thiophenol(0.17 mL, 1.6 mmol) in anhydrous acetonitrile (2.0 mL) was addedpotassium carbonate (0.27 g, 1.9 mmol). The reaction was stirred for 5h. CH₂Cl₂ (10 mL) was then added and the mixture was filtered through acelite pad and concentrated under reduced pressure. This afforded, aftercolumn chromatography (5:95 MeOH/CH₂Cl₂), the desired nosyl-deprotectedproduct (0.75 g, 60%).

To a solution of the above material (75 mg, 0.15 mmol) in anhydrous THF(1.5 mL) was added di-tert-butyldicarbonate (100 mg, 0.45 mmol). Thesolution was allowed to stir for 16 h and then concentrated underreduced pressure. This gave, after radial chromatography (1.5:1.5:97MeOH/NH₄OHCH₂Cl₂), the desired di-boc-protected product (42 mg, 40%). ¹HNMR (CDCl₃) δ 1.32 (br s, 9H), 1.47 (br s, 5H), 1.67 (s, 9H), 1.77 (brs, 4H), 1.97 (m, 1H), 2.15 (m, 2H), 2.29 (m, 1H), 2.73 (m, 6H), 4.22 (m,1H), 4.26 (br s, 2H), 4.53 (d, 1H, J=15.0 Hz), 4.73 (d, 1H, J=15.0 Hz),6.97 (m, 1H), 7.16 (m, 3H), 7.23 (m, 5H), 7.68 (m, 1H), 7.81 (m, 1H),8.36 (d, 1H, J=3.0 Hz).

Using general procedure D: The above material (24 mg, 0.0345 mmol) wasconverted to the hydrobromide salt to provide COMPOUND 85 (26 mg) as awhite solid. ¹H NMR (D₂O) δ 1.82 (br m, 1H), 1.97 (m, 3H), 2.17 (br m,1H), 2.45 (m, 3H), 3.00-3.23 (br m, 5H), 3.38-3.75 (br m, 6H), 4.29 (s,2H), 4.39 (d, 1H, J=16.8 Hz), 4.50 (m, 1H), 4.56 (d, 1H, J=16.8 Hz),7.47 (br s, 5H), 7.60 (m, 2H), 7.79 (m, 2H), 7.83 (t, 1H, J=6.0 Hz),8.32 (d, 1H, J=7.8 Hz), 8.61 (d, 1H, J=5.7 Hz), ¹³C NMR (D₂O) δ 20.29,20.64, 26.15 (2C), 27.65, 46.41, 47.13, 49.13, 51.39 (2C), 51.91, 54.39,60.07, 114.41 (2C), 126.16, 127.06 (2C), 129.82 (2C), 130.16 (2C),130.26, 130.71, 131.30, 139.85 (2C), 140.96, 148.27, 149.95, 150.18.ES-MS m/z 495 (M+H). Anal. Calcd. for C₃₁H₃₈N₆.4.2HBr.3.0H₂O: C, 42.05;H, 5.49; N, 9.49; Br, 37.51. Found: C, 42.13; H, 5.64; N, 9.16; Br,37.53.

Example 86

COMPOUND 86: Preparation of[2-(4-amino-piperidin-1-yl)-ethyl]-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(hydrobromide salt)

To a solution ofN-benzyl-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-2-nitro-benzenesulfonamide(0.62 g, 1.5 mmol) and thiophenol (0.76 mL, 7.4 mmol) in anhydrousacetonitrile (9 mL) was added potassium carbonate (1.22 g, 8.8 mmol).The reaction was stirred for 16 h. The mixture was then filtered througha celite to give, after column chromatography (10:90 MeOH/CH₂Cl₂), thedesired nosyl-deprotected intermediate (0.30 g, 86%).

The above material (0.30 g, 1.3 mmol) was dissolved in anhydrous ethanol(15 mL) and the solution purged with nitrogen gas. 10% palladium oncarbon (130 mg) was added and the reaction mixture was allowed to stirunder a new atmosphere of hydrogen (1 atm) for 16 h. The mixture wasthen filtered through celite to afford a crude yellow residue of2-(4-amino-piperidin-1-yl)-ethanol (0.20 g, quant.).

To a solution of the above material (0.20 g, 1.5 mmol) in anhydrous THF(7.5 mL) was added di-tert-butyldicarbonate (0.37 g, 1.7 mmol). Thesolution was allowed to stir for 16 h and then concentrated underreduced pressure. This afforded, after column chromatography (5:95MeOH/CH₂Cl₂), the desired boc-protected amine (0.14 g, 37%). ¹H NMR(CDCl₃) δ 1.42 (m, 2H), 1.44 (s, 9H), 1.92 (br d, 2H), 2.14 (br t, 2H),2.50 (t, 2H, J=6.0 Hz), 2.82 (br d, 2H), 3.45 (br, 1H), 3.57 (t, 2H,J=6.0 Hz), 4.48 (br, NH).

Methanesulfonyl chloride (60 μL, 0.7 mmol) and triethylamine (0.12 mL,0.9 mmol) was added to a solution of the above material (0.14 g, 0.6mmol) in CH₂Cl₂ (3 mL) at 0° C. and then allowed to warm to roomtemperature over 20 minutes. This gave, after aqueous work up, thedesired methanesulfonate (0.16 g) that was used immediately in the nextreaction without further purification.

Using the general procedure for N-alkylation, the crude methanesulfonate(0.16 g, 0.5 mmol) and(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-ylmethyl]-amine(0.18 g, 0.44 mmol) was stirred at room temperature in acetonitrile (5mL) and diisopropylethylamine (0.13 mL, 0.75 mmol) for 16 hours. Thisyielded, after work-up and column chromatography (5:95 MeOH/CH₂Cl₂), thedesired alkylated product (27 mg, 12%).

The material from above (27 mg, 0.042 mmol) was dissolved in 6N HCl (1mL) and stirred at 50° C. for 3 h. 15% aqueous NaOH (2 mL) was addeduntil pH=12, and the aqueous phase was concentrated under reducedpressure. This gave, after filtering from methanol and radialchromatography (5:1:94 MeOH/NH₄OH/CH₂Cl₂) the desired SEM-deprotectedfree base (12 mg, 69%). ¹H NMR (CDCl₃) δ 1.48 (m, 2H), 1.70 (m, 1H),1.82 (m, 3H), 1.98 (m, 2H), 2.23 (m, 2H), 2.66-2.95 (m, 8H), 3.74 (s,1H), 3.98 (d, 2H, J=15.0 Hz), 4.13 (m, 1H), 7.13 (m, 1H), 7.19 (m, 2H),7.40 (d, 1H, J=9.0 Hz), 7.58 (m, 2H), 8.49 (d, 1H, J=3.0 Hz).

Using general procedure D: The material from above (12 mg, 0.030 mmol)was converted to the hydrobromide salt to provide COMPOUND 86 (14 mg) asa white solid. ¹H NMR (D₂O) δ 1.85-2.05 (br m, 3H), 2.20-2.30 (br m,3H), 2.47 (m, 1H), 3.00 (br m, 2H), 3.15 (br m, 2H), 3.34 (m, 1H),3.44-3.63 (br m, 4H), 4.35 (d, 1H, J=16.5 Hz), 4.47 (m, 1H), 4.53 (d,1H, J=16.5 Hz), 4.80-4.93 (br, 4H), 7.58 (m, 2H), 7.80 (m, 3H), 8.30 (d,1H, J=7.5 Hz), 8.58 (d, 1H, J=5.7 Hz), ¹³C NMR (D₂O) δ 20.30, 20.64,27.29 (2C), 27.65, 45.53, 46.43, 47.14, 51.41 (2C), 54.36, 60.08, 114.44(2C), 126.08, 126.90 (2C), 131.59, 139.88, 140.86 (2C), 148.10, 150.06,150.30. ES-MS m/z 405 (M+H). Anal. Calcd. for C₂₄H₃₂N₆.4.1HBr.3.3H₂O: C,36.41; H, 5.42; N, 10.62; Br, 40.93. Found: C, 36.52; H, 5.49; N, 10.26;Br, 40.94.

Example 87

COMPOUND 87: Preparation of4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyramidine(hydrobromide salt)

[N-(tert-butoxycarbonyl)-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-(3-cyano-prop-1-yl)-amine(0.14 g, 0.30 mmol) was dissolved in anhydrous methanol (3 mL) andanhydrous diethyl ether (5 mL) was added. The solution was cooled to 0°C. and hydrogen chloride gas was bubbled through the solution over 0.5hour to saturation. The reaction was then allowed to stir at roomtemperature for 16 hours, after which the solvent was removed underreduced pressure. The residue was then washed with diethyl ether (3×20mL) and dried in vacuo. This afforded the required4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyrimidicacid methyl ester (hydrochloride salt), which was used immediately inthe next reaction.

The salt from above (0.30 mmol) was dissolved in a solution of ammoniain methanol (2 M, 3 mL, 1.5 mmol), and stirred for 16 hours. Thesolution was then concentrated under reduced pressure and purified bycolumn chromatography (10:1:89 MeOH/NH₄OH/CH₂Cl₂) to give the desired4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyramidinefree base as a crystalline solid (42 mg, 38%, 2 steps). ¹H NMR (CDCl₃) δ1.50 (m, 1H), 1.73-1.95 (br m, 4H), 2.14 (m, 1H), 2.40-2.80 (br m, 6H),3.91 (m, 1H), 3.95 (br d, 1H, J=15.0 Hz), 4.10 (br d, 1H, J=15.0 Hz),7.10 (br, 3H), 7.37 (d, 1H, J=6.0 Hz), 7.55 (br, 2H), 8.44 (br, 1H),8.87 (br, NH), 9.51 (br, NH).

Using general procedure D: The material from above (42 mg, 0.11 mmol)was converted to the hydrobromide salt to provide COMPOUND 87 (28 mg).¹H NMR (D₂O) δ 1.85 (br m, 3H), 1.95 (m, 1H), 2.17 (br m, 1H), 2.37 (t,3H, J=7.8 Hz), 2.56 (m, 1H), 2.86 (m, 1H), 3.00 (br, 2H), 4.37 (d, 1H,J=16.8 Hz), 4.48 (m, 1H), 4.53 (d, 1H, J=16.8 Hz), 7.60 (m, 2H), 7.79(m, 2H), 7.86 (t, 1H, J=6.9 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.62 (d, 1H,J=5.4 Hz); ¹³C NMR (D₂O) δ 20.37, 20.50, 25,60, 27.63, 30.11, 47.89,50.91, 60.41, 114.27 (2C), 126.01, 127.02 (2C), 130.99, 139.43, 140.74(2C), 148.20, 151.41, 152.06. ES-MS m/z 363 (M+H). Anal. Calcd. forC₂₁H₂₆N₆.3.1HBr.1.3H₂O.0.3C₄H₁₀O: C, 40.17; H, 5.27; N, 12.66; Br,37.32. Found: C, 40.09; H, 5.27; N, 12.62; Br, 37.31.

Example 88

COMPOUND 88: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹—(R)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine(crystal)

Solution A: To a solution of anhydrous zinc (II) chloride (70.80 g, 0.52mol) in tetrahydrofuran (320 mL) at room temperature was added sodiumborohydride (17.86 g, 0.47 mol) and the mixture stirred for 1 hour. Thesolution was then chilled to −20° C.

Solution B: To a solution of (R)-(5,6,7,8-tetrahydro-quinolin-8-yl)amine(70.0 g, 0.47 mol) and4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (102.59 g, 0.47mol) in tetrahydrofuran (160 mL) at room temperature was added potassiumcarbonate (65.28 g, 0.47 mol) and the mixture stirred for 1 hour. Thesuspension was then filtered and chilled to −20° C. The cold filtratewas slowly added to Solution A via canula over 35 minutes. The resultingmixture was stirred at −20° C. for 1 hour, until reaction was completeby NMR aliquot. The reaction was then neutralized by the carefuladdition of 6N HCl until pH=2-3, keeping the temperature below −7° C.The solution was then warmed to 22° C. and basified with 13 w/v %Na₂CO_(3(aq)) until pH=4. The tetrahydrofuran was removed under reducedpressure and the concentrate diluted with water (700 mL) and CH₂Cl₂ (530mL). The phases were separated and the organic phase washed withconcentrated ammonium hydroxide (1×230 mL) and water (1×315 mL). Theorganic phase was then concentrated to 200-250 mL and filtered through aconditioned silica gel pad (14 g). The silica gel was rinsed with CH₂Cl₂(2×20 mL). The combined filtrate was concentrated to 100-150 mL anddiluted with diisopropyl ether (1000 mL). The solution was concentratedto 300-350 mL and chilled to −10° C., at which temperature the productbegan to precipitate. Mechanical stirring was continued for 45 minutesat −10° C., after which time the product was collected by filtration.The product was washed with diisopropyl ether (100 mL) and dried underreduced pressure to give pure2-{4-[(R)-(5,6,7,8-tetrahydro-quinolin-8-yl)amino]-butyl}-isoindole-1,3-dione(135.3 g, 82%). ¹H NMR (300 MHz, CDCl₃, δ ppm) 1.55-1.85 (m, 6H),1.95-2.05 (m, 1H), 2.05-2.20 (m, 1H), 2.50 (b, 1H), 2.65-2.85 (m, 4H),3.65-3.80 (m, 3H), 7.04 (dd, 1H, J=4.5 & 7.5 Hz), 7.35 (d, 1H, J=7.5Hz), 7.65-7.75 (m, 2H), 7.75-7.85 (m, 2H), 8.36 (d, 1H, J=4.5 Hz).

To a solution of2-{4-[(R)-(5,6,7,8-tetrahydro-quinolin-8-yl)amino]-butyl}-isoindole-1,3-dione(135.3 g, 0.39 mol) and 2-chloromethyl-benzimidazole-l-carboxylic acidtert-butyl ester (103 g, 0.39 mol) in acetonitrile (780 mL) at roomtemperature was added diisopropylethylamine (101 mL, 0.58 mol) andpotassium iodide (6.4 g, 0.04 mol) and the mixture heated to 50° C. for3 hours. The mixture was then concentrated under reduced pressure andredissolved in methyl t-butyl ether (500 mL) and water (500 mL). The pHwas adjusted to 2 with 6N HCl then the phases were separated. Theaqueous layer was washed with methyl t-butyl ether (500 mL). The aqueousphase was stirred for 22 hours, adding 6N HCl as needed to maintainpH=2. The solution was basified to pH 10-11 with 10N NaOH and extractedwith toluene (2×1.5 L). The organic phase was washed with 1N NaOH (1×200mL) and brine (1×200 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated under reduced pressure to give2-{4-[(R)-(1H-benzimidazol-2-ylmethyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-isoindole-1,3-dione(209 g). ¹H NMR (300 MHz, CDCl₃, δ ppm) 0.75-1.75 (series of m, 5H),1.80-2.10 (2m, 2H), 2.15-2.25 (m, 1H), 2.55-2.90 (m, 4H), 3.52 (t, 2H,J=7.0 Hz), 3.95-4.10 (m, 1H), 4.01 (d, 1H, J=17.0 Hz), 4.11 (d, 1H,J=17.0 Hz), 7.10-7.30 (m, 4H), 7.39 (d, 1H, J=7.5 Hz), 7.50-7.55 (m,1H), 7.60-7.70 (m, 2H), 7.70-7.80 (m, 2H), 8.60 (d, 1H, J=3.5 Hz).

To a solution of2-{4-[(R)-(1H-benzimidazol-2-ylmethyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-isoindole-1,3-dione(209 g, max 0.39 mol) in methanol (2 L) at room temperature was addedhydrazine hydrate (179 mL, 3.12 mol) and the mixture stirred for 16hours. The solution was filtered and the filtrate concentrated. Theresidue was taken up in 1N HCl until pH=2-3. The resulting suspensionwas filtered. The filtrate was basified to pH=6 with 10 N NaOH andwashed with CH₂Cl₂ (2×400 mL). The aqueous phase was further basified topH=12 with 10N NaOH and extracted with CH₂Cl₂ (3×1000 mL). The combinedorganic phase was concentrated under reduced pressure to about 1.4 L.Charcoal (48 g) was added and the suspension stirred for 1 hour. Thecharcoal was removed by filtration and the filtrate was filtered througha dry silica gel pad (140 g). The silica was eluted with 20:1 CH₂Cl₂:MeOH until no more product could be seen by UV (1.0 L). The filtrate waswashed with 0.1N NaOH (1×800 mL), dried (Na₂SO₄), filtered andconcentrated under reduced pressure to give amorphousN¹-(1H-benzimidazol-2-ylmethyl)-N¹—(R)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine(99 g, 73% over two steps). ¹H NMR (300 MHz, CDCl₃, δ ppm) 1.05-1.35 (m,4H), 1.30-1.50 (m, 1H), 1.60-1.85 (2m, 2H), 1.90-2.05 (m, 1H), 2.25-2.70(m, 6H), 3.75-4.00 (m, 3H), 6.90 (dd, 1H, J=4.5 & 7.5 Hz), 6.95-7.05 (m,2H), 7.15 (d, 1H, J=7.5 Hz), 7.35-7.45 (m, 2H), 8.37 (d, 1H, J=4.5 Hz).

AmorphousN¹-(1H-Benzimidazol-2-ylmethyl)-N¹—(R)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine(90.98 g, 0.260 mol) was diluted with ethyl acetate (730 ml, 0.125 g/mL)and heated with stirring until all solids had dissolved (T_(max)=62°C.). The solution was allowed to slowly cool to room temperature whilestirring. Stirring at room temperature was continued for 20 hours. Thecrystals were then collected on a buchner funnel under N₂ atmosphere.The crystals were dried under reduced pressure, then ground with amortar and pestle. The crystals were then dried in a vacuum oven (40°C., greater then 30″ Hg) for two nights to give dryN¹-(1H-benzimidazol-2-ylmethyl)-N¹—(R)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diaminecrystals (69.52 g, 77%). ¹H NMR (CDCl₃) δ 1.21-1.47 (m, 4H), 1.58-1.73(m, 1H), 1.82-2.06 (m, 2H), 2.12-2.23 (m, 2H), 2.45-2.59 (m, 3H),2.64-2.89 (m, 3H), 3.97-4.12 (m, 3H), 7.08-7.20 (m, 3H), 7.49 (d, 1H,J=7.4 Hz), 7.53-7.60 (m, 2H), 8.57 (d, 1H, J=4.2 Hz). ¹³C NMR (CDCl₃) δ21.15, 23.50, 25.78, 28.96, 30.96, 41.61, 49.23, 50.26, 61.62, 114.83,121.22, 121.88, 134.28, 137.01, 146.42, 156.49, 157.39. Purity(HPLC)=99.40%. Enantiomeric Excess (HPLC)=99.66%. Hydrazine (HPLC)=4.7ppm. ES-MS m/z 350 (M+H). Anal Calc. for C₂₁H₂₇N₅: C, 72.17; H, 7.79; N,20.04. Found: C, 71.82; H, 7.74; N, 19.74.

Example 89

COMPOUND 89: Preparation ofN¹-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

To solution of 4,5,6,7-tetrahydro-1H-benzoimidazole (1.9992 g, 16.4mmol) and triethylamine (4.60 mL, 32.8 mmol) in CH₂Cl₂ (20 mL) at 0° C.was added dropwise a solution of dimethyl sulfamoyl chloride (1.76 mL,16.4 mmol) in CH₂Cl₂ (10 mL). The reaction was warmed to roomtemperature and stirred for 3.5 hours. CH₂Cl₂ (80 mL) was added and theorganic phase was washed with distilled water (1×80 mL). The aqueouswashing was extracted with CH₂Cl₂ (2×40 mL), and the combined organicextracts were washed with brine (1×80 mL), dried (Na₂SO₄), andconcentrated. Purification of the crude material by columnchromatography on silica gel (2:1 hexanes-EtOAc) provided 2.89 g (77%)of 4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide as awhite solid. ¹H NMR (CDCl₃) δ 1.77-1.86 (m, 4H), 2.58-2.61 (m, 2H), 2.72(t, 2H, J=6 Hz), 2.87 (s, 6H), 7.77 (s, 1H).

2-Formyl-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamidewas prepared following a modification of the procedure found in theJournal of Medicinal Chemistry, 40; 14, 1997, 2205. To a solution of4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide (2.67 g,11.6 mmol) in dry THF (100 mL) under argon at −78° C. was added dropwise2.5 M n-butyllithium in hexanes (7.0 mL, 17.5 mmol). The reaction wasstirred at −78° C. for 1 hour, then DMF (1.1 mL, 13.9 mmol) was addeddropwise, and the reaction was warmed to room temperature and stirredfor 2 hours. Saturated NH₄Cl (25 mL) was added, and the reaction mixturewas concentrated, and then diluted with CH₂Cl₂ (500 mL) and distilledwater (25 mL). The layers were separated and the aqueous phase wasextracted with CH₂Cl₂ (2×100 mL). The combined organic extracts werewashed with brine (1×100 mL), dried (Na₂SO₄), and concentrated.Purification of the crude material by column chromatography on silicagel (1:1 hexanes-EtOAc) provided 1.53 g (51%) of2-formyl-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamideas a yellow solid. ¹H NMR (CDCl₃) δ 1.82-1.86 (m, 4H), 2.66-2.68 (m,2H), 2.86-2.88 (m, 2H), 2.96 (s, 6H), 9.99 (s, 1H).

To a solution of 2-formyl-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonicacid dimethylamide (0.3991 g, 1.5 mmol) and2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(0.4424 g, 1.3 mmol) in CH₂Cl₂ (13 mL) was added sodiumtriacetoxyborohydride (0.5539 g, 2.6 mmol), and the reaction stirred atroom temperature for 22 hours. Saturated NaHCO₃ (20 mL) was added andthe aqueous phase was extracted with CH₂Cl₂ (2×100 mL), and the combinedorganic extracts were washed with brine (1×75 mL), dried (NaSO₄), andconcentrated. Purification of the crude material by columnchromatography on silica gel (33:1:1 CH₂Cl₂—MeOH—NH₄OH) provided 0.4564g (52%) of2-{[[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonicacid dimethylamide as a yellow foam. ¹H NMR (CDCl₃) δ 1.28 (t, 2H, J=9Hz), 1.49-1.52 (m, 2H), 1.74-1.81 (m, 6H), 1.91-2.00 (m, 1H), 2.11-2.20(m, 1H), 2.50-2.73 (m, 7 H), 2.92 (s, 2H), 2.95 (s, 4H), 3.52-3.57 (m,2H), 4.17-4.22 (m, 2H), 4.32-4.37 (m, 1H), 4.81 (s, 1H), 6.95-6.98 (m,1H), 7.27-7.28 (m, 1H), 7.68-7.70 (m, 2H), 7.79-7.82 (m, 2H), 8.32 (d,1H, J=3 Hz).

2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonicacid (0.4564 g, 0.77 mmol) and 2 N HCl (7.5 mL) were stirred at refluxfor 23 hours. The reaction mixture was cooled to room temperature and15% (w/v) aqueous NaOH (5 mL) was added. The aqueous layer was extractedwith CH₂Cl₂ (3×150 mL), and the combined organic extracts were washedwith brine (1×100 mL), dried (Na₂SO₄), and concentrated. 0.2466 g (64%)of the crude2-{4-[(4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-wino]-butyl}-isoindole-1,3-dionewas isolated as a pale yellow foam. ¹H NMR (CDCl₃) δ 1.37-1.39 (m, 2H),1.79-1.88 (m, 10H), 1.98-2.11 (m, 2H), 2.51-2.63 (m, 8H), 3.50-3.52 (m,1H), 3.66-3.86 (m, 2H), 3.97-3.99 (m, 1H), 7.02-7.11 (m, 2H), 7.37-7.40(m, 2H), 7.68-7.71 (m, 1H), 7.80-7.82 (m, 1H), 8.44-8.46 (m, 1H).

To a solution of2-{4-[(4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione(0.2466 g, 0.51 mmol) in ethanol (5 mL) was added hydrazine hydrate (0.3mL, 2.5 mmol), and stirred at room temperature for 18 hours. Thereaction mixture was concentrated, and purification of the crudematerial by column chromatography on silica gel (20:1:1CH₂Cl₂—MeOH—NH₄OH) provided 0.1031 g (58%) of COMPOUND 89 as a paleyellow solid. ¹H NMR (CDCl₃) δ 1.32-1.43 (m, 5H), 1.60-1.68 (m, 1H),1.72-1.81 (m, 5H), 1.96-2.02 (m, 1H), 2.08-2.17 (m, 1H), 2.45-2.60 (m,9H), 2.69-2.71 (m, 1H), 2.76-2.86 (m, 1H), 3.70-3.84 (m, 2H), 3.95-4.01(m, 1H), 7.05-7.10 (m, 1H), 7.36 (d, 1H, J=7.5 Hz), 8.44 (d, 1H, J=3Hz). ¹³C NMR (CDCL₃) δ 20.80, 22.38, 22.71, 23.07, 25.37, 28.77, 30.54,41.23, 48.53, 49.81, 60.54, 121.36, 133.94, 136.52, 146.20, 146.32,157.37. ES-MS m/z 354.5 (M+H). Anal. Calcd. for(C₂₁H₃₁N₅)0.7(H₂O)0.1(CH₂Cl₂): C, 67.65; H, 8.77; N, 18.69. Found: C,67.46; H, 8.80; N, 18.43.

Example 90

COMPOUND 90: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-2-methylene-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a cold (0° C), stirred solution of AlCl₃ (9.43 g, 70.7 mmol) in Et₂O(250 mL) was added powdered LiAlH₄ (8.10 g, 213 mmol). After theresultant grey suspension was stirred for 40 minutes, a solution ofdimethyl itaconate (8.49 g, 53.7 mmol) in Et₂O (130 mL) was addeddropwise, by cannula, over 30 minutes. The mixture was stirred for anadditional 60 minutes, and then treated with saturated aqueous NH₄Cl(110 mL). The mixture was diluted with Et₂O (500 mL) and filteredthrough filter paper. The filtrate was concentrated and provided 4.52 gof 2-methylene-butane-1,4-diol as a pale yellow oil. To a stirredsolution of 2-methylene-butane-1,4-diol (4.52 g, 44.3 mmol) in CH₂Cl₂(330 mL), at room temperature, was added triethylamine (10.0 mL, 71.7mmol) followed by benzoic anhydride (7.53 g, 33.3 mmol). After 16 hours,the mixture was washed sequentially with 1.0 M HCl (2×35 mL), saturatedaqueous NH₄Cl (2×50 mL), and brine (2×50 mL), dried (Na₂SO₄), andconcentrated. Purification of the crude material by columnchromatography on silica gel (2:1 hexanes-ethyl acetate) provided 3.57 g(32% from dimethyl itaconate) of an ˜5.5:1 mixture of benzoic acid4-hydroxy-2-methylene-butyl ester and benzoic acid3-hydroxymethyl-but-3-enyl ester.

To an ˜5.5:1 mixture of benzoic acid 4-hydroxy-2-methylene-butyl esterand benzoic acid 3-hydroxymethyl-but-3-enyl ester (3.57 g, 17.3 mmol) inCH₂Cl₂ (175 mL) was added Et₃N (6.00 mL, 43.0 mmol) followed bymethanesulfonyl chloride (2.40 mL, 31.0 mmol). The resultant mixture wasstirred at room temperature for 15 hours. The mixture was washed withbrine (3×50 mL), dried (Na₂SO₄), and concentrated. The resultant oil wasdissolved in DMF (90 mL), treated with potassium phthalimide (6.38 g,34.4 mmol), and the resultant mixture was heated at 80° C. for 24 hoursthen cooled to room temperature. The mixture was diluted with ethylacetate (200 mL), brine (90 mL), and water (45 mL) and the phases wereseparated. The organic phase was washed with brine (5×25 mL), dried(MgSO₄), and concentrated. The crude material was purified by columnchromatography on silica gel (4:1 hexanes-ethyl acetate) and provided4.11 g (71%) of an ˜3:1 mixture of benzoic acid4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-methylene-butyl ester andbenzoic acid 3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-but-3-enylester.

To an ˜3:1 mixture of benzoic acid4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-methylene-butyl ester andbenzoic acid 3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-but-3-enylester (4.11 g, 12.3 mmol) in methanol (123 mL) was added NaOH (1.21 g,30.3 mmol) and the mixture was stirred at room temperature for 30minutes. The mixture was diluted with ethyl acetate (250 mL) andsaturated aqueous NaHCO₃ (125 mL). The phases were separated and theaqueous phase was extracted with ethyl acetate (3×100 mL). The combinedorganic extracts were washed with brine (3×30 mL), dried (MgSO₄), andconcentrated. Purification of the crude material by columnchromatography on silica gel (2:1 hexanes-ethyl acetate) provided 0.83 g(29%) of 2-(3-Hydroxymethyl-but-3-enyl)-isoindole-1,3-dione as a whitesolid and 0.19 g (7%) of2-(4-Hydroxy-2-methylene-butyl)-isoindole-1,3-dione as a white solid.

2-(3-Hydroxymethyl-but-3-enyl)-isoindole-1,3-dione: ¹H NMR (CDCl₃) δ2.07 (br s, 1H), 2.49 (t, 2H, J=6.0 Hz), 3.91(t, 2H, J=6.0 Hz), 4.18 (m,2H), 4.79 (s, 1H), 5.01 (s, 1H), 7.70-7.73 (m, 2H), 7.81-7.85 (m, 2H);¹³C NMR (CDCl₃) δ 32.67, 37.04, 66.30, 113.60, 123.30, 132.00, 134.02,145.30, 168.60; ES-MS m/z 231 (M+H).

2-(4-Hydroxy-2-methylene-butyl)-isoindole-1,3-dione: ¹H NMR (CDCl₃) δ1.88 (br s, 1H), 2.36 (t, 2H, J=6.0 Hz); 3.83 (m, 2H), 4.29 (s, 2H),4.99 (s, 1H), 5.02 (s, 1H), 7.72-7.77 (m, 2H), 7.84-7.88 (m, 2H); ¹³CNMR (CDCl₃) δ 37.64, 42.24, 61.21, 114.23, 123.84, 132.37, 134.53,140.73, 168.57; ES-MS m/z 231 (M+H).

To a solution of 2-(3-Hydroxymethyl-but-3-enyl)-isoindole-1,3-dione(0.229 g, 0.99 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (0.28 mL, 2.01mmol) followed by methanesulfonyl chloride (0.12 mL, 1.55 mmol). Theresultant mixture was stirred at room temperature for 1 hour. Themixture was diluted with CH₂Cl₂ (40 mL), washed with brine (3×10 mL),dried (Na₂SO₄), and concentrated to provide 0.31 g (100%) of a yellowoil.

Using General N-alkylation Procedure: A solution of the oil from above(0.31 g),(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.252 g, 0.67 mmol), KI (33 mg, 0.20 mmol), andN,N-diisopropylethylamine (0.35 mL, 2.00 mmol) in CH₃CN (13 mL) washeated at 60° C. for 21 hours. Purification of the crude material bycolumn chromatography on silica gel (50:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided239 mg (60%) of2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-methylene-butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester as a beige foam.

To a solution of2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-methylene-butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (0.239 g, 0.40 mmol) in ethanol (8 mL) was addedhydrazine monohydrate (0.40 mL, 8.26 mmol) and the resultant mixture wasstirred at room temperature overnight. The mixture was filtered throughfilter paper and concentrated. Purification of the crude material bycolumn chromatography on silica gel (20:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided86 mg (55%) of the free base of the title compound as a yellow oil.

Using General Procedure D: Conversion of the free base to thehydrobromide salt followed by reprecipitation of the intermediate solidfrom methanol/ether gave COMPOUND 90 (97 mg, 69%) as a beige solid. ¹HNMR (D₂O) δ 1.75-1.84 (m, 1H), 2.03-2.15 (m, 2H), 2.24-2.40 (m, 3H),2.79-2.88 (m, 1H), 2.94-3.01 (m, 3H), 3.18 (d, 1H, J=13.8 Hz), 3.41 (d,1H, J=13.8 Hz), 4.37 (d, 1H, J=16.5 Hz), 4.48 (d, 1H, J=16.5 Hz),4.59-4.62 (m, 1H), 4.89 (s, 1H), 5.25 (s, 1H), 7.60-7.62 (m, 2H),7.78-7.81 (m, 2H), 7.87-7.91 (m, 1H), 8.37 (br d, 1H, J=7.8 Hz), 8.69(br d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 20.06, 20.30, 27.82, 31.03, 37.47,48.28, 57.13, 60.45, 114.26, 118.52, 126.12, 127.05, 130.93, 139.65,139.79, 141.16, 148.31, 150.83, 151.36; ES-MS m/z 362 (M+H). Anal.Calcd. for C₂₂H₂₇N₅.3.0HBr.2.2H₂O: C, 41.04; H, 5.39; N, 10.88; Br,37.23. Found: C, 40.99; H, 5.25; N, 10.78; Br, 37.21.

Example 91

COMPOUND 91: Preparation of[1-(2-Amino-ethyl)-cyclopropylmethyl]-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

To a cold (0° C.), stirred solution of diethyl zinc (1.0 M in hexanes,4.0 mL, 4.0 mmol) in CH₂Cl₂ (10 mL) was added neat ClCH₂I (0.59 mL, 8.10mmol) drop wise by syringe. After 30 minutes, a solution of2-(3-Hydroxymethyl-but-3-enyl)-isoindole-1,3-dione (0.456 g, 1.97 mmol)in CH₂Cl₂ (6 mL) was added by cannula. After 60 minutes, the reactionmixture was treated with saturated aqueous NH₄Cl (20 mL), diluted withCH₂Cl₂ (20 mL), and warmed to room temperature. The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×20 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated. Thecrude material was purified by column chromatography on silica gel (1:1hexanes-ethyl acetate) and provided 0.31 g (64%) of1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropane-methanolas a white solid. ¹H NMR (CDCl₃) δ 0.31-0.34 (m, 2H), 0.38-0.43 (m, 2H),1.75 (t, 2H, J=6.9 Hz), 3.54 (s, 2H), 3.90(t, 2H, J=6.6 Hz), 7.70-7.73(m, 2H), 7.81-7.85 (m, 2H);

To a solution of1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropane-methanol(0.31 g, 1.26 mmol) in CH₂Cl₂ (6 mL) was added sequentially 3 Åmolecular sieves (0.644 g), N-methylmorpholine N-oxide (0.223 g, 1.90mmol), and tetrapropylammonium perruthenate (88 mg, 0.25 mmol). After 30minutes, the mixture was filtered through silica gel and the cake waswashed with ether. The solvent was removed from the filtrate underreduced pressure and provided 0.25 g (82%) of1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropanecarboxaldehydeas a colorless oil.

Using General Procedure B: Reaction of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.269 g, 0.70 mmol) and1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropanecarboxaldehyde(0.25, 1.03 mmol) with NaBH(OAc)₃ (0.433 g, 2.04 mmol) in CH₂Cl₂ (7 mL)for 6 hours followed by purification of the crude material by columnchromatography on silica gel (50:1:1 CH₂Cl₂—CH₃OH—NH₄OH) followed byradial chromatography on silica gel (1 mm plate, 100:1:1CH₂Cl₂—CH₃OH—NH₄OH) provided 0.125 g (29%) of2-{[{1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropylmethyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester as a white foam.

To a solution of2-{[{1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropylmethyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (0.121 g, 0.20 mmol) in ethanol (4 mL) was addedhydrazine monohydrate (0.20 mL, 4.12 mmol) and the resultant mixture wasstirred at room temperature overnight. The mixture was filtered throughfilter paper and concentrated. Purification of the crude material bycolumn chromatography on silica gel (20:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided39 mg (50%) of the free base of the title compound as a yellow oil.

Using General Procedure D: Conversion of the free base to thehydrobromide salt followed by reprecipitation of the intermediate solidfrom methanol/ether gave COMPOUND 91 (50 mg, 76%) as a white solid. ¹HNMR (D₂O) δ 0.31-0.41 (m, 3H), 0.52-0.58 (m, 1H), 1.34-1.45 (m, 1H),1.75-1.98 (m, 1H), 2.02-2.20 (m, 3H), 2.27-2.33 (m, 1H), 2.44 (d, 1H,J=13.5 Hz), 2.81-2.91 (m, 3H), 2.98-3.01 (m, 2H), 4.39 (s, 2H), 4.69(dd, 1H, J=6.3, 9.3 Hz), 7.60-7.63 (m, 2H), 7.79-7.90 (m, 3H), 8.36(brd, 1H, J=7.8 Hz), 8.71 (br d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ 9.00,12.17, 15.30, 19.79, 20.30, 27.87, 31.06, 37.62, 48.20, 57.47, 59.82,114.31, 126.04, 127.00, 131.20, 139.66, 141.14, 148.20, 151.16, 151.31;ES-MS m/z 376 (M+H). Anal. Calcd. for C₂₃H₂₉N₅.3.0HBr.2.2H₂O: C, 41.99;H, 5.58; N, 10.65; Br, 37.44. Found: C, 42.03; H, 5.41; N, 10.62; Br,36.42.

Example 92

COMPOUND 92 Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-3-methoxy-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-methoxy-butyraldehyde

To a solution of2-[4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-butyl]-isoindole-1,3-dione(seeN¹-(1H-benzimidazol-2-ylmethyl)-3,3-difluoro-N¹-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamineexample for preparation) (455 mg, 1.30 mmol) in neat MeI (2 mL) wasadded Ag₂O (224 mg, 0.97 mmol) and the reaction stirred at 60° C. for 2days. The mixture was cooled, concentrated, diluted with CH₂Cl₂ (10 mL),and filtered through Celite, washing with Et₂O (75 mL). The filtrate wasconcentrated and purified by column chromatography (3:1 hexanes/EtOAc)to afford the methylated product (291 mg, 62%) as a clear oil.

A solution of the TBS-protected alcohol from above (291 mg, 0.80 mmol)in THF/1 N HCl (1:1, 7 mL) was stirred for 3 h. The mixture was dilutedwith EtOAc (35 mL) and water (10 mL) and saturated aqueous ammoniumchloride (10 mL). The phases were separated and the organic phase waswashed with brine (1×25 mL), dried (Na₂SO₄) and concentrated to give thecrude product (242 mg) as a clear oil which was used without furtherpurification in the next reaction.

To a solution of the alcohol from above (242 mg) in CH₂Cl₂ (10 mL) wasadded 3 Å molecular seives (265 mg), NMO (137 mg, 1.17 mmol) and TPAP(25 mg, 0.071 mmol) and the reaction stirred 1.5 h. The mixture wasconcentrated and purified by flash chromatography (EtOAc/hexanes, 1:2)to afford the title compound (95 mg, 48% over 2 steps) as a clear solid.¹H NMR (CDCl₃) δ 2.65-2.69 (m, 2H), 3.46 (s, 3H), 3.82 (t, 2H, J=6 Hz),4.02-4.08 (m, 1H), 7.74 (dd, 2H, J=6, 3 Hz), 7.86 (dd, 2H, J=6, 3 Hz),9.78 (s, 1H).

Following General Procedure B: To a stirred solution(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(108 mg, 0.39 mmol) and4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-methoxy-butyraldehyde (95 mg,0.385 mmol) in dry CH₂Cl₂ (10 mL) was added NaBH(OAc)₃ (125 mg, 0.59mmol) and the mixture stirred for 2.5 h at room temperature. Theresultant crude yellow foam (230 mg) was used without furtherpurification in the next step.

To a solution of the phthalimide from above (0.38 mmol) in EtOH (3.5 mL)was added anhydrous hydrazine (0.06 mL, 1.89 mmol) and the mixturestirred overnight. The resultant white solid was filtered through filterpaper, washing thoroughly with CH₂Cl₂ and the filtrate concentrated invacuo. The crude product was purified by radial chromatography on silicagel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH, 50:1:1 then 25:1:1) to give thedesired free amine (85 mg, 58% 2 steps) as a pale yellow oil.

Using General Procedure D: Conversion of the material from above (78 mg,0.21 mmol) to the hydrobromide salt gave COMPOUND 92 (124 mg, 89%) as ayellow solid. ¹H NMR (D₂O) mixture of diastereomers δ 1.81-1.86 (br m,3H), 2.01-2.07 (m, 1H), 2.18-2.24 (m, 1H), 2.37-2.42 (m, 1H), 2.54-2.63(m, 1H), 2.88-3.10 (m, 5H), 3.24 (s, 3H), 3.51-3.56 (m, 1H), 4.40 (d,1H, J=16.8 Hz), 4.50-4.58 (m, 2H), 7.60 (dd, 2H, J=6.3, 3.3 Hz), 7.81(dd, 2H, J=6.3, 3.3 Hz), 7.88 (br t, 1H, J=6.8 Hz), 8.36 (d, 1H, J=8.1Hz), 8.63-8.66 (m, 1H); ¹³C NMR (D₂O) mixture of diastereomers δ 20.43,27.65, 29.90, 30.52, 42.10, 47.48, 48.01, 48.20, 57.04, 57.28, 60.47,75.71, 75.92, 114.30, 126.02, 127.00, 131.01, 139.45, 140.69, 140.78,148.21, 151.06, 151.51. ES-MS m/z 380 (M+H). Anal. Calcd. forC₂₂H₂₉N₅O.3.1HBr.1.5H₂O.0.3C₄H₁₀O: C, 41.00; H, 5.65; N, 10.31; Br,36.45. Found: C, 41.01; H, 5.62; N, 10.34; Br, 36.39.

Example 93

COMPOUND 93: Preparation ofN¹-(1H-benzimidazol-2-ylmethyl)-3,3-difluoro-N¹-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine

To a mixture of potassium phthalimide (310.39 g, 1.68 mol) in DMF (1.0L) at 0° C. was added allyl bromide (290.4 mL, 3.36 mol) from a droppingfunnel over 30 minutes. The reaction was then warmed to room temperatureand allowed to stir for 5 days. The mixture was filtered to remove saltswhile washing the residue with ethyl acetate (1 L), and the filtrateconcentrated under reduced pressure. The residue was then partitionedbetween saturated aqueous NaHCO₃ (0.5 L) and CH₂Cl₂ (0.8 L) and theorganic phase separated. The aqueous phase was extracted with CH₂Cl₂(2×0.8 L), and the combined organic phases were dried (Na₂SO₄), filteredand concentrated under reduced pressure to give N-allylphthalimide as awhite powder (294 g, 94%). ¹H NMR (CDCl₃) δ 4.30 (d, 2H, J=6.0 Hz), 5.22(m, 2H), 5.88 (m, 1H), 7.73 (m, 2H), 7.85 (m, 2H).

A solution of paraformaldehyde (245 g) was heated to 70° C. in asolution of H₂SO₄ (360 mL) and H₂O (90 mL) using a hot water bath untilthe mixture became homogenous. Solid N-allylphthalimide (133 g, 0.71mol) was then added over 10 minutes, keeping the exotherm generatedunder control. The solution was then stirred at this temperature for anadditional 0.5 hour and poured into ice water (1.5 L). The mixture wasextracted with ethyl acetate (3×1 L), dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude solid was then purifiedthrough a silica gel plug (1 kg SiO₂) from CH₂Cl₂ as the eluent. Thisafforded the desired 1,3-dioxane-4-ylmethylphthalimide as a white solid(95 g, 54%).

1,3-dioxane-4-ylmethylphthalimide (95 g, 390 mmol) was dissolved in asaturated solution of hydrochloric acid in methanol (600 mL) and stirredfor 2 days at 80° C. The reaction was then cooled to room temperature,and the acid neutralised to pH 7 with solid NaHCO₃. Ethyl acetate (1 L)was added and the mixture was filtered to remove salts. The filtrate wasthen concentrated under reduced pressure and dried overnight in vacuo.The crude was purified through a silica gel plug (1 kg silica) using2:98 CH₃OH:CH₂Cl₂ eluent to give the desiredN-(2,4-dihydroxybutyl)phthalimide as a white solid (45 g, 50%). ¹H NMR(MeOD) δ 1.62 (m, 1H), 1.75 (m, 1H), 3.31 (s, 1H), 3.64 (m, 2H), 3.69(d, 2H, J=5.1 Hz), 4.06 (sept, 1H), 7.79 (m, 2H), 7.85 (m, 2H).

To a solution of N-(2,4-dihydroxybutyl)phthalimide (51 g, 217 mmol) inpyridine (725 mL) at 0° C. was added acetic anhydride (20.5 mL, 217mmol). The solution was stirred at 0° C. for 4 hours and thenconcentrated on the rotary evaporator using a water bath temperature of35° C. The crude residue was then purified through a silica gel plug (1kg silica) with 0.5:99.5 CH₃OH:CH₂Cl₂ eluent to give the desired productwhich was unfortunately contaminated with pyridine. CH₂Cl₂ (100 mL) wasthen added and the organic was washed with 1N HCl (3×50 mL), saturatedaqueous NH₄Cl (50 mL), and brine (50 mL). The organic phase was thenseparated, dried (Na₂SO₄), filtered, and concentrated under reducedpressure to afford clean N-(4-acetoxy-2-hydroxybutyl)phthalimide as awhite solid (10.2 g, 17%).

A solution of N-(4-acetoxy-2-hydroxybutyl)phthalimide (10.2 g, 36.8mmol) in CH₂Cl₂ (185 mL) at 0° C. was treated with molecular seives(18.4 g), N-methylmorpholine oxide (6.46 g, 55.2 mmol), andtetrapropylammonium perruthenate (1.29 g, 3.7 mmol). The mixture wasallowed to warm to room temperature over 20 minutes and immediatelyfiltered through silica (using 500 g SiO₂ in a coarse glass frittedfunnel). The silica was washed with excess diethyl ether (2 L) andconcentrated under reduced pressure to afford the desiredN-(4-acetoxy-2-oxobutyl)phthalimide (9.22 g, 92%).

The above ketone (8.0 g, 29 mmol) was added as dry solid to neat DAST(20 mL) at 0° C. and then heated to 50° C. for 40 hours. The homogenoussolution was then cooled to 0° C., diluted with CH₂Cl₂ (75 mL), andquenched with excess brine (50 ml). The organic phase was separated andthe aqueous phase extracted with CH₂Cl₂ (3×75 mL). The combined organicphases were then dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude red solid was then purified by column chromatographyon silica gel (1:4 ethyl acetate/hexane) to give the desiredN-(4-acetoxy-2,2-difluorobutyl)phthalimide as a peach colored solid(3.84 g, 44%). ¹H NMR (CDCl₃) δ 2.07 (s, 3H), 2.32 (tt, 2H, J=16.5, 6.0Hz), 4.11 (t, 2H, J=13.5 Hz), 4.35 (t, 2H, J=7.5 Hz), 7.75 (m, 2H), 7.90(m, 2H).

The above N-(4-acetoxy-2,2-difluorobutyl)phthalimide (3.84 g, 12.9 mmol)was dissolved in THF (65 mL) and cooled to −78° C. A solution of DIBAL-H(32.3 mL, 1.0 M in hexanes, 32.3 mmol) was added slowly and the solutionallowed to stir 0.5 h. Saturated aqueous NH₄Cl solution (15 mL) was thenadded and the solution was warmed to room temperature. MgSO₄ (15 g) anddiethyl ether (200 mL) were added, and the mixture was filtered throughcelite, washing with excess 1:1 Et₂O/THF (1 L). The filtrate was thenconcentrated under reduced pressure and the crude material was purifiedby column chromatography on silica gel (1:2 EtOAc/hexanes) to give thedesired N-(2,2-difluoro-4-hydroxybutyl)phthalimide as a pale yellowsolid (1.47 g, 45%). ¹H NMR (CDCl₃) δ 1.97 (t, OH, J=6.0 Hz), 2.22 (tt,2H, J=16.5, 6.0 Hz), 3.95 (q, 2H, J=6.0 Hz), 4.19 (t, 2H, J=15 Hz), 7.75(m, 2H), 7.90 (m, 2H).

Methanesulfonyl chloride (0.50 mL, 6.3 mmol) and triethylamine (1.20 mL,8.6 mmol) was added to a solution of the above alcohol (1.47 g, 5.76mmol) in CH₂Cl₂ (29 mL) at 0° C. and allowed to warm to room temperatureover 30 minutes. This gave, after aqueous work up, the desired crudemethanesulfonate (1.84 g, 96%) as a fine, pale yellow powder that wasused immediately in the next reaction.

A solution of the above crude methanesulfonate (1.84 g) in DMF (19 mL)was treated with sodium azide (1.87 g, 28.8 mmol) and heated to 80° C.for 2 h. The reaction mixture was then concentrated and the residuepartitioned between ethyl acetate (20 mL) and brine (15 mL). The organicphase was separated, washed with brine (3×15 mL), and dried over MgSO₄.The mixture was then filtered and concentrated under reduced pressure togive the desired N-(4-azido-2,2-difluorobutyl)phthalimide (1.37 g, 85% 2steps).

The material from above (1.37 g) was dissolved in anhydrous methanol (50mL) and the reaction vessel purged with nitrogen. 10% palladium oncarbon (275 mg) was added and the mixture stirred under an atmosphere ofhydrogen (30 psi) for 16 hours. The reaction mixture was then filteredthrough celite and purified by column chromatography with silica gel(2:98 methanol:dichloromethane) to affordN-(4-amino-2,2-difluorobutyl)phthalimide (0.71 g, 57%). ¹H NMR (CDCl₃) δ2.32 (tt, 2H, J=16.5, 6.0 Hz), 3.02 (t, 2H, J=15.0 Hz), 3.94 (t, 2H,J=7.5 Hz), 7.73 (m, 2H), 7.85 (m, 2H).

Using general procedure B from above,N-(4-amino-2,2-difluorobutyl)phthalimide (0.28 g, 1.1 mmol),6,7-dihydro-5H-quinolin-8-one (0.21 g, 1.4 mmol) and sodiumtriacetoxyborohydride (0.45 g, 2.2 mmol) were stirred at roomtemperature in dichloromethane (5.5 mL) for 16 hours to yield, afterwork-up and column chromatography (2:98 MeOH:CH₂Cl₂),2-[2,2-difluoro-4-(5,6,7,8-tetrahydroquinolin-8-ylamino)-butyl]-isoindole-1,3-dioneas a sticky oil (0.36 g, 85%).

To a solution of the above secondary amine (0.36 g, 0.93 mmol),N-(tert-butoxycarbonyl)-2-chloromethylbenzimidazole (0.25 g, 0.93 mmol),and potassium iodide (8 mg, 0.05 mmol) in anhydrous acetonitrile (9.3mL) was added diisopropylethylamine (0.24 mL, 1.4 mmol) and stirred at60° C. for 16 hours. The mixture was then concentrated under reducedpressure and the residue partitioned between dichloromethane (20 mL) andbrine (15 mL). The organic phase was separated and the aqueous phase wasextracted with dichloromethane (2×15 mL). The combined organic phaseswere then dried (Na₂SO₄), filtered, and concentrated under reducedpressure to give a crude residue that was purified by columnchromatography with silica gel (2:98 MeOH/CH₂Cl₂). This afforded2-{[[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3,3-difluorobutyl]-(5,6,7,8-tertahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (0.24 g, 41%).

A solution of the above substrate (0.24 g, 0.39 mmol) in anhydrousethanol (3.7 mL) was treated with hydrazine monohydrate (0.20 mL, 3.9mmol) and stirred for 16 h. The white mixture was then filtered,concentrated under reduced pressure, and purified by columnchromatography with silica gel (5:0.5:94.5 methanol:ammoniumhydroxide:dichloromethane) to affordN-(1H-benzimidazol-2-ylmethyl)-3,3-difluoro-N-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamineas a light beige solid (87 mg, 66%). ¹H NMR (CDCl₃) δ 1.67 (m, 1H),1.70-2.20 (m, 4H), 2.28 (m, 1H), 2.55-3.00 (m, 5H), 3.10 (m, 1H), 4.12(m, 1H), 4.26 (s, 2H), 7.20 (m, 3H), 7.45 (d, 1H, J=7.5 Hz), 7.59 (br,2H), 8.61 (d, 1H, J=3.9 Hz). ¹³C NMR (CDCl₃) δ 21.88, 24.85, 29.49,35.88 (t, 1C, J=20 Hz), 38.24 (t, 1C, J=92 Hz), 51.74, 55.25 (t, 1C,J=116Hz), 62.99, 115.41 (br, 3C), 122.14(2C), 122.92, 125.40, 128.61,135.29, 137.93, 147.10, 155.75, 156.98. ES-MS m/z 385 (M+H). Anal.Calcd. for C₂₁H₂₅N₅F₂.0.2CH₂Cl₂: C, 63.27; H, 6.36; N, 17.40. Found: C,63.27; H, 6.60; N, 17.26.

Example 94

COMPOUND 94: Preparation ofN¹-(1H-benzimidazol-2-ylmethyl)-2,2-difluoro-N¹-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine

To a solution of N-(4-amino-2,2-difluorobutyl)phthalimide (0.33 g, 1.3mmol) in anhydrous THF (7 mL) was added di-tert-butyldicarbonate (0.31g, 1.4 mmol) and a drop of water. The solution was stirred 30 minutesand saturated aqueous ammonium chloride solution (25 mL) was added andthe solution was extracted with ethyl acetate (2×30 mL). The combinedorganic phases were then dried (MgSO₄), filtered, and concentrated underreduced pressure. This afforded the crude boc-protected primary amine asyellow solid (0.42 g, 91%).

A solution of the above amine (0.42 g, 1.2 mmol) in anhydrous ethanol(12 mL) was treated with hydrazine monohydrate (0.57 mL, 12 mmol) andstirred for 16 h. The turbid white mixture was then filtered,concentrated under reduced pressure, and purified by columnchromatography with silica gel (1:1:10 methanol:ammoniumhydroxide:dichloromethane) to give (4-amino-3,3-difluorobutyl)-carbamicacid tert-butyl ester (0.21 g, 77%). ¹H NMR (CDCl₃) δ 1.30 (br, NH₂),1.45 (s, 9H), 2.01 (tt, 2H, J=16.5, 6.0 Hz), 2.95 (t, 2H, J=6.0 Hz),3.52 (td, 2H, J=15.0, 7.0 Hz), 5.00 (br, NH).

Using general procedure B from above,N-(4-amino-2,2-difluorobutyl)phthalimide (0.26 g, 1.2 mmol),6,7-dihydro-5H-quinolin-8-one (0.22 g, 1.5 mmol) and sodiumtriacetoxyborohydride (0.49 g, 2.3 mmol) were stirred at roomtemperature in dichloromethane (5.5 mL) for 16 hours to yield, afterwork-up and column chromatography (1:99 MeOH:CH₂Cl₂),[3,3-difluoro-4-(5,6,7,8-tetrahydroquinolin-8-ylamino)-butyl]-carbamicacid tert-butyl ester as a sticky oil (0.37 g, 90%).

To a solution of the above secondary amine (0.37 g, 1.0 mmol),N-(tert-butoxycarbonyl)-2-chloromethylbenzimidazole (0.44 g, 1.7 mmol),and potassium iodide (9 mg, 0.05 mmol) in anhydrous acetonitrile (10.0mL) was added diisopropylethylamine (0.36 mL, 2.1 mmol) and stirred at60° C. for 16 hours. The mixture was then concentrated under reducedpressure and the residue partitioned between dichloromethane (20 mL) andbrine (15 mL). The organic phase was separated and the aqueous phase wasextracted with dichloromethane (2×15 mL). The combined organic phaseswere then dried (Na₂SO₄), filtered, and concentrated under reducedpressure to give a crude residue that was purified by columnchromatography with silica gel (2:98 MeOH/CH₂Cl₂). This afforded2-{[(4-tert-butoxycarbonylamino-2,2-difluorobutyl)-(5,6,7,8-tertahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester as a pale yellow solid (0.23 g, 41%).

A solution of the above material (0.23 g, 0.4 mmol) in neat TFA (4 mL)was stirred for 0.5 h. The solution was diluted with CH₂Cl₂ (20 mL), and15% aqueous NaOH was added until pH>10. The organic phase was separated,and the aqueous was extracted with CH₂Cl₂ (2×20 mL). The combinedorganic phases were then dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. This afforded, after radial chromatography(2:1:97 MeOH:NH₄OH:CH₂Cl₂),N-(1H-benzimidazol-2-ylmethyl)-2,2-difluoro-N-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamineas a pale yellow flaky solid (0.11 g, 72%). ¹H NMR (CDCl₃) δ 1.69 (m,1H), 1.85-2.10 (m, 4H), 2.23 (m, 1H), 2.70-2.97 (m, 6H), 4.03 (d, 1H,J=17.1 Hz), 4.07 (m, 1H), 4.15 (d, 1H, J=16.8 Hz), 7.15-7.24 (m, 3H),7.45 (d, 1H, J=7.8 Hz), 7.58 (br, 2H), 8.57 (d, 1H, J=3.9 Hz). ¹³C NMR(CDCl₃) δ 21.62, 24.35, 29.47, 34.03 (t, 1C, J=93 Hz), 44.55 (t, 1C,J=20 Hz), 47.26 (t, 1C, J=112 Hz), 50.12, 62.87, 118 (br, 3C), 122.09(2C), 122.80, 123.86, 127.06, 135.10, 137.99, 147.06, 156.27, 157.41.ES-MS m/z 385 (M+H). Anal. Calcd. for C₂₁H₂₅N₅F₂.0.2CH₂Cl₂: C, 63.27; H,6.36; N, 17.40. Found: C, 63.34; H, 6.68; N, 17.29.

Example 95

COMPOUND 95: Preparation of(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-2-(O-methyloxime)-butan-4-yl)-amine

To a solution of 3-buten-1-ol (10 g, 138 mmol) in dichloromethane (150mL) was added acetic anhydride (13 mL, 138 mmol) and4-dimethylaminopyridine (244 mg, 2 mmol). The mixture was then stirredat room temperature for 8 hours. The reaction mixture was then pouredinto a saturated aqueous sodium bicarbonate solution (100 mL). Afterseparation of the aqueous and organic layers, the aqueous layer wasextracted twice with 100 mL portions of dichloromethane. The combinedorganic fractions were then dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to afford 3-buten-1-yl acetate as acolourless oil in a yield of 12.9 g (82%). ¹H NMR (CDCl₃) δ 2.04 (s,3H), 2.38 (m, 2H), 4.11 (t, 3H, J=7.1 Hz), 5.04 (d, 1H, J=9.1 Hz), 5.08(d, 1H, J=15.3 Hz), 5.77 (m, 1H).

To a solution of 3-buten-1-yl acetate (5.7 g, 50 mmol) indichloromethane (200 mL) was added m-chloroperoxybenzoic acid (12.9 g,75 mmol). The reaction was then stirred at room temperature for 3 hours.The reaction mixture was then filtered through celite and concentratedin vacuo. The residue was purified by silica gel flash chromatography(4:1 hexanes:ethyl acetate) to yield 3,4-epoxybutan-1-yl acetate as acolourless oil in a yield of 3.8 g (58%). ¹H NMR (CDCl₃) δ 1.78-1.88 (m,2H), 2.03 (s, 3H), 2.47 (m, 1H), 2.75 (m, 1H), 2.99 (m, 1H), 4.18 (t,1H, J=6.6 Hz).

To a solution of 3,4-epoxybutan-1-yl acetate (3.9 g, 29 mmol) in DMF (50mL) was added potassium phthalimide (6.47 g, 35 mmol). The stirredmixture was then heated to 90° C. for 16 hours. After cooling, themixture was diluted with ethyl acetate (200 mL) and extracted repeatedlywith water. The organic fraction was then dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bysilica gel flash chromatography (1:1 hexanes:ethyl acetate) to affordN-(3-hydroxybutan-4-yl-1-acetate)-phthalimide as a pale yellow oil in ayield of 1.65 g (20%). ¹H NMR (CDCl₃) δ 1.69-1.88 (m, 2H), 2.04 (s, 3H),2.90 (m, 1H(OH)), 3.79 (d, 2H, J=5.7 Hz), 4.03 (m, 1H), 4.21-4.31 (m,2H), 7.70 (m, 2H), 7.83 (m, 2H). MS m/z 300 (M+Na).

To a solution of afford N-(3-hydroxybutan-4-yl-1-acetate)-phthalimide(554 mg, 2.0 mmol) in acetonitrile (15 mL) was added imidazole (150 mg,2.2 mmol) and t-butyldimethylsilyl chloride (310 mg, 2.05 mmol). Themixture was then stirred overnight at room temperature. Dichloromethane(50 mL) was then added to the reaction, and the mixture was extractedwith a saturated ammonium chloride solution. The organic layer was thendried over anhydrous sodium sulfate, filtered and concentrated to leavea yellow oily residue which was purified by silica gel flashchromatography (3:1 hexanes:ethyl acetate) to affordN-(3-t-butyldimethylsiloxybutan-4-yl-1-acetate)-phthalimide in a yieldof 570 mg (73%). ¹H NMR (CDCl₃) δ −0.04 (s, 3H), −0.01 (s, 3H), 0.84 (s,9H), 1.78 (m, 2H), 3.68 (dd, 1H, J=8.1, 6.5 Hz), 3.73 (dd, 1H, J=8.1,6.2 Hz), 4.15 (m, 3H), 7.71 (m, 2H), 7.85 (m, 2H).

To a stirred −78° C. solution of affordN-(3-t-butyldimethylsiloxybutan-4-yl-1-acetate)-phthalimide (670 mg,1.71 mmol) in THF (20 mL) was added DIBAL-H (5.1 mL of a 1.0M solutionin hexanes, 5.1 mmol). The reaction was stirred at −78° C. for 45minutes, then a saturated solution of ammonium chloride (5 mL) wasadded. The mixture was allowed to warm to room temperature, then ethylacetate (20 mL) and 1N HCl (2 mL) were added. The mixture was thenshaken in a separatory funnel to speed the clarification of the layers,then the organic and aqueous layers were separated. The aqueous layerwas extracted twice with ethyl acetate, then the combined organicfractions were separated and the aqueous layer was extracted twice withethyl acetate. The combined organic fractions were then dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by silica gel flash chromatography (1:1hexanes:ethyl acetate) to affordN-(3-t-butyldimethylsiloxybutan-1-ol-4-yl)-phthalimide as a colourlessoil in a yield of 465 mg (78%). ¹H NMR (CDCl₃) δ −0.02 (s, 3H), 0.09 (s,3H), 0.86 (s, 9H), 1.71-1.82 (m, 2H), 2.11 (m, 1H(OH)), 3.76 (m, 4H),4.28 (m, 1H), 7.73 (m, 2H), 7.85 (m, 2H).

To a solution of N-(3-t-butyldimethylsiloxybutan-1-ol-4-yl)-phthalimide(160 mg, 0.4 mmol) in dichloromethane (10 mL) was added Dess-MartinPeriodinane (212 mg, 0.5 mmol). The mixture was then stirred at roomtemperature for 30 minutes. A 5% solution of sodium thiosulfate (10 mL)and a saturated sodium bicarbonate solution (10 mL) was added along withanother 20 mL of dichloromethane. The mixture was then stirred rapidlyfor 20 minutes, and the aqueous and organic layers were separated. Theaqueous layer was extracted twice with dichloromethane, and the combinedorganic fractions were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to affordN-(3-t-butyldimethylsiloxybutan-1-al-4-yl)-phthalimide as a yellow oil,which was used immediately in the next reaction without furtherpurification. ¹H NMR (CDCl₃) δ −0.02 (s, 3H), 0.05 (s, 3H), 0.81 (s,9H), 2.61 (m, 2H), 3.74 (m, 2H), 4.51 (m, 1H), 7.71 (m, 2H), 7.85 (m,2H), 9.81 (m, 1H).

To a solution of N-(3-t-butyldimethylsiloxybutan-1-al-4-yl)-phthalimide(0.4 mmol) in dichloromethane (15 mL) was added(5,6,7,8-tetrahydroquinolin-8-yl)-[(N-t-butoxycarbonyl)-benzimidazol-2-yl)methyl]-amine(151 mg, 0.4 mmol). The mixture was stirred at room temperature for 30minutes, then sodium triacetoxyborohydride (170 mg, 0.8 mmol) was added,and the reaction was allowed to stir for 16 hours. A saturated sodiumbicarbonate solution (10 mL) was added, and the aqueous and organiclayers were separated. The aqueous layer was then extracted twice withdichloromethane, and the combined organic fractions were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was then purified by silica gel flash chromatography (3%methanol in dichloromethane) to afford[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-2-(t-butyldimethylsiloxy)-4-yl)-amineas a pale yellow foam in a yield of 224 mg (79%). ¹H NMR (CDCl₃) δ −0.25(s, 3H), −0.23 (s, 3H), 0.69 (s, 9H), 1.44-1.63 (m, 4H), 1.68 (s, 9H),2.00 (m, 2H), 2.16 (m, 1H), 2.65-2.74 (m, 3H), 3.48-3.62 (m, 2H), 3.94(m, 1H), 4.23 (m, 1H), 4.44 (d, 1H, J=15.3 Hz), 4.72 (m, 1H, J=15.3 Hz),6.95 (m, 1H), 7.20 (m, 3H), 7.67 (m, 3H), 7.77 (m, 3H), 8.44 (m, 1H).

To a solution of[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-2-(t-butyldimethylsiloxy)-4-yl)-amine(170 mg, 0.24 mmol) in THF (8 mL) was added 1N HCl (2 mL). The mixturewas then heated to 50° C. for 2 hours. After cooling, dichloromethane(50 mL) was added, and the mixture was shaken with a saturated sodiumbicarbonate solution (20 mL). After separation of the aqueous andorganic layers, the aqueous layer was extracted twice withdichloromethane. The combined organic fractions were then dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to afford afoamy residue, which was purified by silica gel flash chromatography (5%methanol in dichloromethane) to afford(1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-2-ol-4-yl)-amineas a white foam in a yield of 73 mg (49%). ¹H NMR (CDCl₃) δ 1.50-1.59(m, 2H), 1.70-2.07 (m, 5H), 2.21 (m, 1H), 2.75-3.00 (m, 4H), 3.78-3.94(m, 2H), 4.00-4.22 (m, 2H), 7.04 (m, 1H), 7.16 (m, 2H), 7.24 (d, 1H,J=5.8 Hz), 7.68 (br s, 1H (NH)), 7.71 (m, 3H), 7.81 (m, 3H), 8.21 and8.42 (d, total of 1H, J=4.9, 5.1 Hz respectively).

To a solution of(1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-2-ol-4-yl)-amine(132 mg, 0.246 mmol) in dichloromethane (10 mL) was added Dess MartinPeriodinane (145 mg, 0.344 mmol). The reaction mixture was then stirredfor 60 minutes. A 5% Na₂S₂O₃/5% NaHCO₃ aqueous solution (10 mL) was thenadded, and the resulting mixture was stirred vigorously at roomtemperature for 20 minutes (until the aqueous and organic layers hadclarified). The layers were then separated, and the aqueous layer wasextracted twice with dichloromethane. The combined organic fractionswere then dried over anhydrous sodium sulfate, filtered andconcentrated, and the residue was purified by silica gel flashchromatography (5% methanol in dichloromethane) to give the desiredproduct,(1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-2-one-4-yl)-amineas a pale yellow foam in a yield of 109 mg (84%). ¹H NMR (CDCl₃) δ 1.73(m, 1H), 1.85 (m, 1H), 2.03 (m, 1H), 2.26 (m, 1H), 2.57-2.81 (m, 4H),3.10 (m, 1H), 4.08 (s, 2H), 4.08 (m, 1H), 4.35 (d, 1H, J=16.5 Hz), 4.63(d, 1H, J=16.5 Hz), 7.00 (m, 1H), 7.19 (m, 2H), 7.18 (m, 1H), 7.38 (brs, 1H(NH)), 7.75 (m, 4H), 7.88 (m, 2H), 8.56 (m, 1H).

To a solution of(1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-2-one-4-yl)-amine(58 mg, 0.117 mmol) in methanol (5 mL) was added hydroxylaminehydrochloride (83.5 mg, 1.0 mmol). The resulting solution was stirred atroom temperature overnight. Aqueous sodium bicarbonate (5 mL of asaturated solution) was then added, dichloromethane (10 mL) was alsoadded the aqueous and organic layers were separated and the aqueouslayer was extracted twice with dichloromethane. The combined organicfractions were then dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel flashchromatography using a 5% methanol in dichloromethane mixture as aneluent to afford(1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-2-(O-methyloxime)-4-yl)-amineas a pale yellow foam in a yield of 29 mg (49%). ¹H NMR (CDCl₃) δ1.73-2.05 (series of m, 5H), 2.45 (t, 2H, J=6.9 Hz), 2.87-2.98 (m, 4H),3.16 and 3.79 (s, total of 3H), 4.01-4-12 (m, 3H), 4.26 and 4.30 (d,J=16.7 and 16.9 Hz respectively, total of 1H), 4.47 and 4.85 (d, J=16.7and 16.9 Hz respectively, total of 1H), 7.13-7.17 (m, 2H), 7.25 (m, 2H),7.22 (m, 1H), 7.60 (br s, 1H(NH)), 7.75 (m, 4H), 7.87 (m, 2H), 8.38 and8.44 (m, total of 1H).

To a solution of(1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-2-(O-methyloxime)-4-yl)-amine(29 mg, 0.055 mmol) in denatured ethanol (5 mL) was added hydrazinehydrate (0.07 mL, 1.5 mmol). The mixture was then heated to 60° C. for60 minutes. After cooling, the reaction was concentrated in vacuo, takenup in dichloromethane (20 mL) and washed with an aqueous sodiumcarbonate solution (5 mL). The aqueous layer was then extracted twicewith dichloromethane, and the combined organic fractions were dried overanhydrous sodium sulfate, filtered and concentrated to afford a foamyresidue which was purified by silica gel flash chromatography (10%methanol, 0.5% ammonium hydroxide in dichloromethane) to afford(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-2-(O-methyloxime)-butan-4-yl)-amine(COMPOUND 95—diastereomeric mixture) as a white foam in a yield of 10mg. ¹H NMR (CDCl₃) δ 1.65 (m, 1H), 1.98 (m, 1H), 2.02 (m, 1H) 2.19 (m,1H), 2.42 (m, 2H), 2.78-2.87 (m, 4H), 3.31 (m, 2H), 3.55 and 3.73 (s,3H), 4.03 (m, 3H), 7.13 (m, 3H), 7.40 (t, 1H, J=8.1 Hz), 7.56 (m, 2H),8.51 and 8.51 (d, J=5.4 Hz, 5.3 Hz respectively, total of 1H); ¹³C NMR(both isomers—CDCl₃) δ 21.77, 23.51, 27.85, 29.58, 32.47, 43.34, 47.55,49.09, 49.62, 49.94, 53.81, 61.60, 62.02, 122.07, 122.61, 132.33,134.41, 137.79, 142.65, 147.04, 154.98.

Example 96

COMPOUND 96: Preparation of(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-2-(cyclopropanyl)-butan-4-yl)-amine

To an ˜7:1 mixture of benzoic acid 4-hydroxy-2-methylene-butyl ester andbenzoic acid 3-hydroxymethyl-but-3-enyl ester (0.705 g, 3.42 mmol) inCH₂Cl₂ (17 mL) was added Et₃N (1.00 mL, 7.17 mmol) followed bytert-butyldimethylsilyl chloride (0.792 g, 5.25 mmol) and4-(dimethylamino)pyridine (84 mg, 0.69 mmol). The mixture was stirred atroom temperature for 2 hours, diluted with CH₂Cl₂ (50 mL), washed withbrine (3×20 mL), dried (Na₂SO₄), and concentrated. Purification of thecrude material by column chromatography on silica gel (25:1hexanes-ethyl acetate) provided 1.00 g (92%) of an ˜7:1 mixture ofbenzoic acid 4-(tert-butyldimethylsilyloxy)-2-methylene-butyl ester andbenzoic acid 3-(tert-butyldimethylsilyloxymethyl)-but-3-enyl ester as acolorless oil.

To an ˜7:1 mixture of benzoic acid4-(tert-butyldimethylsilyloxy)-2-methylene-butyl ester and benzoic acid3-(tert-butyldimethylsilyloxymethyl)-but-3-enyl ester (1.00 g, 3.13mmol) in methanol (31 mL) was added NaOH (0.306 g, 7.64 mmol) and themixture was stirred at room temperature for 2 hours. The mixture wasdiluted with ethyl acetate (75 mL) and saturated aqueous NaHCO₃ (20 mL).The phases were separated and the organic phase was washed with brine(2×10 mL), dried (MgSO₄), and concentrated. Purification of the crudematerial by column chromatography on silica gel (9:1 hexanes-ethylacetate) provided 0.58 g (58%) of4-(tert-butyldimethylsilyloxy)-2-methylene-butan-1-ol as a colorlessoil. ¹H NMR (CDCl₃) δ 0.06 (s, 6H), 0.90 (s, 9H), 2.34 (t, 2H, J=6.0Hz); 2.78 (br s, 1H), 3.75 (t, 2H, J=6.0 Hz), 4.07-4.11 (m, 2H), 4.90(s, 1H), 5.04 (s, 1H);

To a cold (0° C.), stirred solution of diethyl zinc (1.0 M in hexanes,4.0 mL, 4.0 mmol) in CH₂Cl₂ (8 mL) was added neat ClCH₂I (0.58 mL, 7.96mmol) drop wise by syringe. After 1 hour, a solution of4-(tert-butyldimethylsilyloxy)-2-methylene-butan-1-ol (0.395 g, 1.83mmol) in CH₂Cl₂ (4 mL) was added by cannula. After 30 minutes, thereaction mixture was treated with saturated aqueous NH₄Cl (10 mL),diluted with CH₂Cl₂ (12 mL), and warmed to room temperature. The phaseswere separated and the aqueous phase was extracted with CH₂Cl₂ (3×10mL). The combined organic extracts were dried (Na₂SO₄) and concentrated.The crude material was purified by column chromatography on silica gel(9:1 hexanes-ethyl acetate) and provided 0.41 g (97%) of{1-[2-(tert-butyldimethylsilyloxy)-ethyl]-cyclopropyl}-methanol as acolorless oil.

To solution of{1-[2-(tert-butyldimethylsilyloxy)-ethyl]-cyclopropyl}-methanol (0.41 g,1.78 mmol) in CH₂Cl₂ (18 mL) was added Et₃N (0.50 mL, 3.59 mmol)followed by methanesulfonyl chloride (0.21 mL, 2.71 mmol). The resultantmixture was stirred at room temperature for 17 hours. The mixture wasdiluted CH₂Cl₂ (50 mL), washed with brine (3×20 mL), dried (Na₂SO₄), andconcentrated. The resultant oil was dissolved in DMF (16 mL), treatedwith potassium phthalimide (0.606 g, 3.27 mmol), and the mixture washeated at 80° C. for 6 hours then cooled to room temperature. Themixture was diluted with ethyl acetate (40 mL), brine (20 mL), and water(10 mL) and the phases were separated. The organic phase was washed withbrine (3×10 mL), dried (MgSO₄), and concentrated. The crude material waspurified by column chromatography on silica gel (20:1 hexanes-ethylacetate) and provided 0.24 g (38%) of2-{1-[2-(tert-butyldimethylsilyloxy)-ethyl]-cyclopropylmethyl}-isoindole-1,3-dioneas a colorless oil.

To a solution of2-{1-[2-(tert-butyldimethylsilyloxy)-ethyl]-cyclopropylmethyl}-isoindole-1,3-dione(0.24 g, 0.68 mmol) in THF (3 mL) was added 1.0 M HCl (3 mL). Theresultant solution was stirred, at room temperature, for 3 hours. Themixture was diluted with saturated aqueous NH₄Cl (10 mL) and extractedwith CH₂Cl₂ (3×20 mL). The combined organic extracts were dried (Na₂SO₄)and concentrated. The crude material was purified by columnchromatography on silica gel (2:1 hexanes-ethyl acetate) and provided0.146 g (88%) of2-[1-(2-hydroxy-ethyl)-cyclopropylmethyl]-isoindole-1,3-dione as a whitesolid. ¹H NMR (CDCl₃) δ 0.29-0.35 (m, 2H), 0.59-0.62 (m, 2H), 1.41 (t,2H, J=6.6 Hz), 2.80 (br s, 1H), 3.53 (s, 2H), 3.76 (t, 2H, J=6.6 Hz),7.59-7.63 (m, 2H), 7.69-7.74 (m, 2H);

To a solution of the alcohol from above (146 mg, 0.595 mmol) indichloromethane (15 mL) was added Dess-Martin Periodinane (303 mg, 0.715mmol). The mixture was then stirred at room temperature for 45 minutes.A 5% solution of sodium thiosulfate (10 mL) and a saturated sodiumbicarbonate solution (10 mL) was added along with another 20 mL ofdichloromethane. The mixture was then stirred rapidly for 20 minutes,and the aqueous and organic layers were separated. The aqueous layer wasextracted twice with dichloromethane, and the combined organic fractionswere dried over anhydrous sodium sulfate, filtered and concentrated invacuo to afford N-(3-cyclopropanyl-butan-1-al-4-yl)-phthalimide as ayellow foam, which was used immediately in the next reaction withoutfurther purification. ¹H NMR (CDCl₃) δ 0.43 (m, 2H), 0.86 (m, 2H), 2.40(s, 2H), 3.65 (s, 2H), 7.68 (m, 2H), 7.83 (m, 2H), 9.79 (s, 1H).

To a solution of N-(3-cyclopropanyl-butan-1-al-4-yl)-phthalimide (0.595mmol) in dichloromethane (15 mL) was added(5,6,7,8-tetrahydroquinolin-8-yl)-[(N-t-butoxycarbonyl)-benzimidazol-2-yl)methyl]-amine(227 mg, 0.6 mmol). The mixture was stirred at room temperature for 30minutes, then sodium triacetoxyborohydride (254 mg, 1.2 mmol) was added,and the reaction was allowed to stir for 16 hours. A saturated sodiumbicarbonate solution (10 mL) was added, and the aqueous and organiclayers were separated. The aqueous layer was then extracted twice withdichloromethane, and the combined organic fractions were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was then purified by silica gel flash chromatography (3%methanol in dichloromethane) to afford[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(N-phthalimidyl)-butan-2-(cyclopropanyl)-4-yl]-amineas a pale yellow foam in a yield of 130 mg (36%). ¹H NMR (CDCl₃) δ 0.23(m, 2H), 0.55 (m, 2H), 1.15 (m, 1H), 1.35 (m, 1H), 1.66 (s, 9H), 1.70(m, 2H), 2.00 (m, 2H), 2.16 (m, 1H), 2.69 (m, 1H), 2.97 (m, 2H), 3.31(d, 1H, J=15.3 Hz), 3.51 (d, 1H, J=15.3 Hz), 4.23 (m, 1H), 4.43 (d, 1H,J=17.1 Hz), 4.62 (d, 1H, J=17.1 Hz), 7.00 (m, 1H), 7.23 (m, 4H), 7.65(m, 2H), 7.74 (m, 2H), 7.74 (m, 1H), 8.38 (m, 1H).

To a solution of[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-(N-phthalimidyl)-butan-2-(cyclopropanyl)-4-yl)-amine(187 mg, 0.31 mmol) in ethanol (8 mL) was added hydrazine hydrate (0.1mL). The mixture was then heated to 60° C. for 60 minutes. Aftercooling, the reaction was concentrated in vacuo, taken up indichloromethane (20 mL) and washed with an aqueous sodium carbonatesolution (5 mL). The aqueous layer was then extracted twice withdichloromethane, and the combined organic fractions were dried overanhydrous sodium sulfate, filtered and concentrated to afford a foamyresidue which was purified by silica gel flash chromatography (10%methanol, 0.5% ammonium hydroxide in dichloromethane) to afford(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(1-amino-2-(cyclopropanyl)-butan-4-yl)-amineas a white foam in a yield of 100 mg (86%). ¹H NMR (CDCl₃) δ 0.17 (s,2H), 0.25 (s, 2H), 1.32 (m, 1H), 1.61 (m, 2H), 1.85 (m, 1H), 1.93 (m,1H), 2.19 (m, 1H), 2.39 (s, 1H), 2.86 (m, 4H), 3.99 (m, 4H), 5.40 (br s,2H(NH₂)), 7.03 (dd, 1H, J=4.8, 8.1 Hz), 7.15 (m, 2H), 7.32 (d, 1H, J=8.1Hz), 7.54 (m, 2H), 8.48 (d, 1H, J=4.8 Hz).

Following General Procedure D: To a solution of(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(1-amino-2-(cyclopropanyl)-butan-4-yl)-amine(100 mg, 0.267 mmol) in glacial acetic acid (2 mL) was added a saturatedsolution of HBr in acetic acid (0.5 mL) to yield, after precipitationand drying,(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(1-amino-2-(cyclopropanyl)-butan-4-yl)-amine(HBr salt—COMPOUND 96) as a cream-coloured powder (126 mg, 69%). ¹H NMR(D₂O) δ 0.36 (m, 1H), 0.52 (m, 2H), 1.31 (m, 1H), 1.75 (m, 2H), 2.01 (m,1H), 2.06 (m, 1H), 2.63 (m, 1H), 2.64 (d, 1H, J=13.5 Hz), 2.87 (d, 1H,J=13.5 Hz), 2.99 (m, 3H), 4.36 (d, 1H, J=16.8 Hz), 4.55 (m, 1H), 4.49(d, 1H, J=16.8 Hz), 7.60 (m, 2H), 7.79 (m, 2H), 7.85 (dd, 1H, J=7.8, 5.4Hz), 8.32 (d, 1H, J=7.8 Hz), 8.60 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ11.39, 11.52, 17.02, 20.44, 27.64, 32.22, 45.79, 47.91, 49.32, 49.82,60.58, 114.26, 125.98, 126.97, 130.98, 139.32, 140.69, 148.15, 151.17,151.72. ES-MS m/z 376 (M+H). Anal. Calcd. forC₂₃H₂₉N₅×1.4H₂O×3.1HBr×0.4Et₂O: C, 43.37; H, 5.76; N, 10.28; Br, 36.36.Found: C, 43.41; H, 5.73; N, 10.27; Br, 36.37.

Example 97

COMPOUND 97: Preparation of(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-2-methyl-but-2-en-4-yl)-amine

To a solution of N-(3-methylenyl-butan-1-ol-4-yl)-phthalimide (180 mg,0.83 mmol—(See preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-2-methylene-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine,hydrobromide salt for details)) in dichloromethane (15 mL) was addedDess-Martin Periodinane (424 mg, 1.0 mmol). A 5% solution of sodiumthiosulfate (10 mL) and a saturated sodium bicarbonate solution (10 mL)was added along with another 20 mL of dichloromethane. The mixture wasthen stirred rapidly for 20 minutes, and the aqueous and organic layerswere separated. The aqueous layer was extracted twice withdichloromethane, and the combined organic fractions were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to affordN-(3-methylenyl-butan-1-al-4-yl)-phthalimide as a yellow foam, which wasused immediately in the next reaction without further purification. ¹HNMR (CDCl₃) δ 3.19 (s, 2H), 4.32 (s, 2H), 5.07 (s, 1H), 5.24 (s, 1H),7.70 (m, 2H), 7.84 (s, 2H), 9.66 (s, 1H).

To a solution of N-(3-methylenyl-butan-1-al-4-yl)-phthalimide (0.83mmol) in dichloromethane (15 mL) was added(5,6,7,8-tetrahydroquinolin-8-yl)-[(N-t-butoxycarbonyl)-benzimidazol-2-yl)methyl]-amine(227 mg, 0.6 mmol). The mixture was stirred at room temperature for 30minutes, then sodium triacetoxyborohydride (254 mg, 1.2 mmol) was added,and the reaction was allowed to stir for 16 hours. A saturated sodiumbicarbonate solution (10 mL) was added, and the aqueous and organiclayers were separated. The aqueous layer was then extracted twice withdichloromethane, and the combined organic fractions were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was then purified by silica gel flash chromatography (3%methanol in dichloromethane) to afford[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(N-phthalimidyl)-2-methyl-but-2-en-4-yl]-amineas a pale yellow foam in a yield of 88 mg (26%). ¹H NMR (CDCl₃) δ 1.26(s, 3H) 1.48 (m, 3H), 1.68 (s, 9H), 2.04 (m, 1H), 2.74 (m, 2H), 3.47(dd, 1H, J=13.1, 5.9 Hz), 3.61 (dd, 1H, J=13.1, 5.9 Hz), 4.19 (m, 1H),4.33 (d, 1H, J=16.1 Hz), 4.49 (d, 1H, J=16.1 Hz), 5.43 (t, 1H, J=5.9Hz), 6.95 (m, 1H), 7.13 (m, 2H), 7.64 (m, 2H), 7.73 (m, 2H), 7.81 (m,2H), 8.22 (m, 1H), 8.61 (m, 1H).

To a solution of[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(N-phthalimidyl)-2-methyl-but-2-en-4-yl]-amine 88 mg, 0.15 mmol) inethanol (8 mL) was added hydrazine hydrate (0.1 mL). The mixture wasthen heated to 60° C. for 60 minutes. After cooling, the reaction wasconcentrated in vacuo, taken up in dichloromethane (20 mL) and washedwith an aqueous sodium carbonate solution (5 mL). The aqueous layer wasthen extracted twice with dichloromethane, and the combined organicfractions were dried over anhydrous sodium sulfate, filtered andconcentrated to afford a foamy residue which was purified by silica gelflash chromatography (10% methanol, 0.5% ammonium hydroxide indichloromethane) to afford[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-amino-2-methyl-but-2-en-4-yl]-amineas a white foam in a yield of 33 mg (61%). ¹H NMR (CDCl₃) δ 1.57 (s,9H), 1.71 (m, 1H), 1.89 (m, 1H), 2.01 (m, 2H), 2.27 (m, 1H), 2.74 (m,3H), 3.01 (s, 3H), 3.16 (dd, 1H, J=7.1, 4.3 Hz), 3.31 (dd, 1H, J=7.1,4.3 Hz), 4.02 (m, 3H), 5.30 (m, 1H), 7.13 (m, 4H), 7.40 (d, 1H, J=7.8Hz), 7.54 (m 1H), 8.54 (d, 1 H, J=4.8 Hz).

To a solution of[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-amino-2-methyl-but-2-en-4-yl]-amine(33mg, 0.091 mmol) in glacial acetic acid (2 mL) was added a saturatedsolution of HBr in acetic acid (0.5 mL). The resulting mixture wasstirred and treated as per standard procedure D to yield, afterprecipitation and drying,[(1H-benzimidazol-2-yl)methyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-amino-2-methyl-but-2-en-4-yl]-amine(HBr salt—COMPOUND 97) as a cream-coloured powder (28 mg, 46%). ¹H NMR(D₂O) δ 1.63 (s, 3H), 1.83 (m, 1H), 2.06 (m, 1H), 2.17 (m, 1H), 2.40 (m,1H), 3.01 (m, 5H), 3.21 (m, 1H), 4.30 (d, 1H, J=16.8Hz), 4.48 (d, 1H,J=16.8Hz), 4.49 (m, 1H), 5.47 (t, 1H, J=5.8 Hz), 7.60 (m, 2H), 7.79 (m,2H), 7.80 (m, 1H), 8.33 (d, 1H, J=7.8 Hz), 8.63 (d, 1H, J=5.1 Hz); ¹³CNMR (D₂O) δ 14.12, 20.41, 20.69, 27.63, 46.26, 48.25, 49.15, 60.97,114.24, 125.95, 127.10, 127.52, 130.87, 132.88, 139.45, 140.69, 148.08,151.08, 151.73. ES-MS m/z 362 (M+H). Anal. Calcd. forC₂₂H₂₅N₅×1.5H₂O×3.1HBr×0.5Et₂O: C, 42.62; H, 5.68; N, 10.35; Br, 36.62.Found: C, 42.37; H, 5.31; N, 10.18; Br, 36.31.

Example 98

COMPOUND 98: Preparation of(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-2-methylenyl-butan-4-yl)-amine

To a solution of N-(3-methylenyl-butan-1-ol-4-yl)-phthalimide (209 mg,0.90 mmol—(See preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-2-methylene-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine,hydrobromide salt, for details) in dichloromethane (5 mL) wasmethanesulfonyl chloride (0.092 mL, 1.2 mmol). The mixture was thenstirred for 30 minutes at room temperature before being treated withaqueous ammonium chloride (5 mL). The layers were then separated, andthe aqueous layer was washed twice with 10 mL fractions ofdichloromethane. The combined organic fractions were then dried overanhydrous sodium sulfate and concentrated. The residue was taken up inDMF (5 mL) to which sodium azide (25 mg, 0.38 mmol) was added. Themixture was then heated to 80° C. and was stirred overnight. Thereaction was then cooled and poured into ethyl acetate (100 mL). Thesolution was then extracted repeatedly (5×) with distilled water. Theorganic layer was then dried over anhydrous sodium sulfate andconcentrated. The residue was purified by silica gel flashchromatography using a 1:1 mixture of ethyl acetate:hexanes as aneluent. The product ¹-N-phthalimidyl-(2-methylenyl-butan-4-yl)-azide wascollected as a white solid. ¹H NMR (CDCl₃) δ 2.36 (t, 2H, J=6.9 Hz),3.49 (t, 2H, J=6.9 Hz), 4.13 (s, 2H), 5.03 (s, 1H), 5.08 (s, 1H), 7.72(m, 2H), 7.88 (m, 2H).

To a solution of [1-N-phthalimidyl-(2-methylenyl-butan-4-yl)]-azide(199mg, 0.78 mmol) in methanol (20 mL) was added palladium on calciumcarbonate (Lindlar's Catalyst, 40 mg). The mixture was then placed under1 atm hydrogen gas and was stirred rapidly for 3 hours. The mixture wasthen filtered and concentrated to afford the product[1-(N-phthalimidyl)-2-methylenyl-butan-4-yl]-amine as a yellow gum (160mg, 84%). ¹H NMR (CDCl₃) δ 3.32 (t, 2H, J=7.1 Hz), 3.76 (t, 2H, J=7.1Hz), 4.28 (s, 2H), 5.14 (s, 1H), 5.30 (s, 1H), 7.70 (m, 2H), 7.82 (m,2H).

To a solution of [1-(N-phthalimidyl)-2-methylenyl-butan-4-yl]-amine (160mg, 0.658 mmol) in dichloromethane (8 mL) was added5,6,7,8-tetrahydroquinoline-8-one (58 mg, 0.4 mmol). The mixture wasstirred at room temperature for 30 minutes, then sodiumtriacetoxyborohydride (348 mg, 1.65 mmol) was added, and the reactionwas allowed to stir for 16 hours. A saturated sodium bicarbonatesolution (10 mL) was added, and the aqueous and organic layers wereseparated. The aqueous layer was then extracted twice withdichloromethane, and the combined organic fractions were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was then purified by silica gel flash chromatography (3%methanol in dichloromethane) to afford(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(N-phthalimidyl)-2-methylenyl-butan-4-yl]-amineas a pale yellow foam in a yield of 75 mg (52%). ¹H NMR (CDCl₃) δ 1.74(m, 1H), 2.02 (m, 1H), 2.52 (m, 2H), 2.77 (m, 4H), 3.41 (d, 1H, J=7.7Hz), 3.55 (d, 1H, J=7.7 Hz), 3.78 (m, 3H), 4.86 (m, 1H), 5.05 (1H), 7.04(m, 1H), 7.37 (m, 1H), 7.68 (m, 2H), 7.80 (m, 2H), 8.36 (m, 1H).

To a solution of(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(N-phthalimidyl)-2-methylenyl-butan-4-yl]-amine(75 mg, 0.21 mmol) in acetonitrile (5 mL) was addedN-t-butoxycarbonyl-2-chloromethylbenzimidazole (80 mg, 0.3 mmol).Di-isopropylethylamine (0.052 mL, 0.3 mmol) was then added, and theresulting solution was warmed to 70° C. and was stirred overnight. Aftercooling, a saturated ammonium solution (10 mL), and dichloromethane (30mL) was added, and the aqueous and organic layers were separated. Theaqueous layer was then extracted twice with dichloromethane, and thecombined organic fractions were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was then purified bysilica gel flash chromatography (3% methanol in dichloromethane) toafford[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(N-phthalimidyl)-2-methylen-4-yl]-amineas a pale yellow foam in a yield of 62 mg (50%). ¹H NMR (CDCl₃) δ 1.68(s, 9H), 1.89 (m, 1H), 2.03 (m, 2H), 2.11 (m, 1H), 2.40 (t, 2H, J=6.9Hz), 2.75 (m, 2H), 3.27 (d, 1H, J=13.1 Hz), 3.46 (d, 1H, J=13.1 Hz),3.61 (m, 2H), 4.11 (m, 1H), 4.48 (d, 1H, J=16.1 Hz), 4.63 (d, 1H, J=16.1Hz), 6.95 (m, 1H), 7.23 (m, 2H), 7.64 (m, 2H), 7.76 (m, 3H), 8.61 (m,2H).

To a solution of[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(N-phthalimidyl)-2-methylen-4-yl]-amine(62 mg, 0.10 mmol) in ethanol (8 mL) was added hydrazine hydrate (0.1mL). The mixture was then heated to 80° C. for 60 minutes. Aftercooling, the reaction was concentrated in vacuo, taken up indichloromethane (20 mL) and washed with an aqueous sodium carbonatesolution (5 mL). The aqueous layer was then extracted twice withdichloromethane, and the combined organic fractions were dried overanhydrous sodium sulfate, filtered and concentrated to afford a foamyresidue which was purified by silica gel flash chromatography (10%methanol, 0.5% ammonium hydroxide in dichloromethane) to afford[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(amino)-2-methylen-4-yl]-amineas a white foam in a yield of 29 mg (74%). ¹H NMR (CDCl₃) δ 1.64 (m,1H), 1.89-2.02 (m, 3H), 2.08 (m, 1H), 2.35 (m, 2H), 2.77 (m, 1H), 2.81(m, 1H), 2.94 (m, 1H), 3.04 (d, 1H, J=13.1 Hz), 3.16 (d, 1H, J=13.1 Hz),4.03 (m, 3H), 4.87 (s, 1H), 5.06 (s, 1H), 7.12 (m, 3H), 7.40 (d, 1H,J=8.1 Hz), 7.57 (m, 2H), 8.58 (m, 1H).

To a solution of[(N-t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(amino)-2-methylen-4-yl]-amine(29mg, 0.080 mmol) in glacial acetic acid (2 mL) was added a saturatedsolution of HBr in acetic acid (0.5 mL). The resulting mixture wasstirred and treated as per standard procedure D to yield, afterprecipitation and drying,[(1H-benzimidazol-2-yl)methyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(amino)-2-methylen-4-yl]-amine(HBr salt—COMPOUND 98) as a cream-coloured powder (28 mg, 55%). ¹H NMR(D₂O) δ 1.81 (m, 1H), 2.05 (m, 2H), 2.23 (m, 3H), 2.79 (m, 1H), 2.94 (m,3H), 3.18 (d, 1H, J=14.1 Hz), 3.41 (d, 1H, J=14.1 Hz), 4.34 (d, 1H,J=16.1 Hz), 4.48 (d, 1H, J=16.1 Hz), 4.60 (m, 1H), 5.26 (m, 2H), 7.53(m, 2H), 7.79 (m, 2H), 7.89 (dd, 1H, J=5.1, 7.8 Hz), 8.54 (d, 1H, J=7.8Hz), 8.68 (d, 1H, J=5.1 Hz); ³C NMR (D₂O) δ 20.05, 20.29, 27.81, 31.02,37.45, 48.26, 57.09, 60.44, 114.26, 118.49, 126.09, 127.01, 131.00,139.67, 139.79, 141.13, 148.25, 150.85, 151.38. ES-MS m/z 362 (M+H).Anal. Calcd. for C₂₂H₂₅N₅×1.8 H₂O×3.0 HBr: C, 41.50; H, 5.32; N, 11.00;Br, 37.65. Found: C, 41.54; H, 5.17; N, 10.85; Br, 37.55.

Example 99

COMPOUND 99: Preparation of(1H-benzimidazol-4-methoxy-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(1-aminobutan-4-yl)-amine

To a 0° C. solution of potassium t-butoxide (5.87g, 52.3 mmol) in DMF(40 mL) under an inert atmosphere of argon was added copper (I) chloride(0.2 g, 2.0 mmol). The resulting suspension was stirred for 10 minutes,then a solution of 3-nitroanisole (1.55 g, 10.1 mmol) and methoxylaminehydrochloride (1.08 g, 12.9 mmol) in DMF (15 mL) was added in a dropwisemanner over 15 minutes. The mixture was then allowed to slowly warm toroom temperature and was stirred for 48 hours. Water (20 mL) was thenadded to the reaction, and the mixture was poured into a separatoryfunnel containing 100 mL ethyl acetate. The aqueous and organic layerswere then separated, and the organic layer was extracted 5 times with 20mL portions of water. The organic layer was then dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified bysilica gel flash chromatography using a 3:1 hexanes:ethyl acetatemixture as an eluent. Three isomeric products were isolatedconsecutively from the column, the first being the desired2-amino-3-nitroanisole, which was isolated as an orange powder in ayield of 465 mg (29%). ¹H NMR (CDCl₃) δ 3.95 (s, 3H), 6.44 (br s,2H(NH)), 6.61 (dd, 1H, J=7.8, 7.1 Hz), 6.87 (d, 1H, J=7.1 Hz), 7.73 (d,1H, J=7.8 Hz)

To a solution of 2-amino-3-nitroanisole (465 mg, 2.94 mmol) in methanol(50 mL) was added palladium on carbon (10% Pd, 100 mg). The mixture wasthen placed under an atmosphere of hydrogen gas (1 atm) and was stirredfor one hour. The mixture was then filtered through celite andconcentrated to give 2,3-diaminoanisole as a yellow foam in a yield of400 mg (98%). ¹H NMR (CDCl₃) δ 3.45 (br s, 4H(NH)), 3.84 (s, 3H), 6.40(m, 2H), 6.67 (t, 1H, J=7.8 Hz)

A solution of 2,3-diaminoanisole (400 mg, 2.89 mmol) and chloroaceticacid (557 mg, 6 mmol) in 4 N HCl was heated to 105° C. for 16 hours. Themixture was then cooled, neutralized (to a pH of 8) with aqueous sodiumbicarbonate, and extracted twice with dichloromethane. The organicfractions were then dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel flashchromatography using a 1:1 mixture of hexanes:ethyl acetate as an eluentto give 1H-2-chloromethyl-4-methoxybenzimidazole as a yellow foam in ayield of 386 mg (68%). ¹H NMR (CDCl₃) δ 3.96 (s, 3H), 4.85 (s, 2H), 6.71(m, 1H), 7.19 (m, 2H).

To a solution of 1H-2-chloromethyl-4-methoxybenzimidazole (138 mg, 0.7mmol) and(5,6,7,8-tetrahydroquinolin-8-yl)-(1-(N-phthalimidyl)-butan-4-yl)-amine(180 mg, 0.515 mmol) in acetonitrile (8 mL) was addeddi-isopropylethylamine (0.13 mL, 0.75 mmol). The resulting solution washeated to 70° C. for 6 hours. The reaction was then cooled, andpartitioned between aqueous ammonium chloride and dichloromethane. Afterseparation of the layers, the aqueous layer was extraced twice withdichloromethane. The combined organic fractions were then dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by silica gel flash chromatography using a 5% methanol indichloromethane solution as an eluent. The product(1H-benzimidazol-4-methoxy-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(N-phthalimidyl)-aminobutan-4-yl]-aminewas isolated as a pale yellow foam in a yield of 212 mg (8268 (m, 4H),1.90-2.05 (m, 2H), 2.03 (m, 2H), 2.61-2.83 (m, 4H), 3.80-4.10 (m, 8H),6,60 (m, 1H), 7.06 (m, 3H), 7.63 (m 1H), 7.63-7.77 (m, 4H), 8.40 (m,1H).

To a solution of product(1H-benzimidazol-4-methoxy-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(N-phthalimidyl)-aminobutan-4-yl]-amine(212 mg, 0.417 mmol) in denatured ethanol (10 mL) was added hydrazinehydrate (0.25 mL). The resulting mixture was heated to 80° C. for 60minutes, then cooled and concentrated. The residue was filtered througha silica gel plug (5 g silica) using a 10:1 dichloromethane:methanolmixture as an eluent. The collected eluent (200 mL) was thenconcentrated, re-dissolved in THF (10 mL) and di-t-butyl carbonate (212mg, 1.0 mmol) was added. The mixture was then stirred at roomtemperature overnight. The reaction was then concentrated, and theresidue was purified by silica gel flash chromatography using a 5%methanol in dichloromethane mixture as an eluent to afford the desired(1-t-butoxycarbonyl-benzimidazol-4-methoxy-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(N-t-butoxycarbonyl)-aminobutan-4-yl]-amineas a pale foam in a yield of 68 mg (28%). ¹H NMR (CDCl₃) δ 1.18-1.23 (m,4H), 1.39 (s, 9H), 1.70 (s, 9H), 1.97-2.07 (m 4H), 2.58-2.95 (m, 6H),4.01 (s, 3H), 4.18 (m, 1H), 4.58 (m, 2H), 4.92 (br s, 1H(NH)), 6.72 (d,1H, J=8.1 Hz), 6.91 (m, 1H), 7.16 (m, 2H), 7.35 (d, 1H, J=8.1 Hz), 8.33(m, 1H).

(1-t-butoxycarbonyl-benzimidazol-4-methoxy-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(N-t-butoxycarbonyl)-aminobutan-4-yl]-amine(68 mg, 0.117 mmol) was taken up in acetic acid (1 mL), to which asaturated solution of HBr in acetic acid (0.1 mL) was added. The mixturewas then stirred, precipitated and isolated as per procedure D to yieldCOMPOUND 99 as a white crystalline solid in a yield of 49 mg (65%). ¹HNMR (D₂O). δ 1.52 (m, 4H), 1.79 (m, 1H), 1.98 (m, 1H), 2.14 (m, 1H),2.35 (m, 1H), 2.53 (m, 1H), 2.79 (m, 3H), 2.99 (m, 2H), 4.03 (s, 3H),4.36 (d, 1H, J=16.8 Hz), 4.49 (m, 1H), 4.50 (d, 1H, J=16.8 Hz), 7.10 (d,1H, J=8.1 Hz), 7.34 (d, 1H, J=8.4 Hz), 7.51 (t, 1H, J=8.4 Hz), 7.85 (dd,1H, J=8.1, 5.4 Hz), 8.34 (d, 1H, J=8.1 Hz), 8.60 (d, 1H, J=5.4 Hz). ¹³CNMR (D₂O) δ 20.44, 20.84, 25.05, 25.41, 27.66, 39.54, 48.10, 51.76,56.70, 60.54, 106.20, 107.45, 121.85, 125.90, 128.14, 132.39, 139.30,140.56, 147.45, 148.05, 150.89, 151.30. ES-MS m/z 380 (M+H); Anal.Calcd. for (C₂₂H₂₉N₅O×3.0 HBr×1.0 H₂O): C, 41.27; H, 5.35; N, 10.94; Br37.44. Found: C, 41.28; H, 5.33; N, 10.67; Br, 37.24.

Example 100

COMPOUND 100: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(4-methoxy-5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

8-amino-4-methoxy-5,6,7,8-tetrahydroquinoline was prepared in 68% yieldfrom 8-hydroxy-4-methoxy-5,6,7,8-tetrahydroquinoline (preparation andcharacterization described by: Uchida, M.; Morita, S.; Chihiro, M.;Kanbe, T.; Yamasaki, K.; Yabuuchi, Y.; Nakagawa, K. Chem. Pharm. Bull.1989, 37, 1517-1523.) using the same procedure employed to prepare8-amino-5,6,7,8-tetrahydroquinoline (according to the proceduresdescribed in Bridger et al. U.S. patent application U.S. Ser. No.09/535,314). ¹H NMR (CDCl₃) δ 1.59-2.15 (m, 6H), 2.60-2.65 (m, 2H), 3.84(s, 3H), 3.95 (dd, 1H, J=6.0, 9.0 Hz), 6.61 (d, 1H, J=6.0 Hz). 8.32 (d,1H, J=6.0 Hz); ¹³C NMR (CDCl₃) δ 19.53, 22.89, 31.94, 51.57, 55.62,104.04, 120.94, 148.52, 160.42, 163.71; ES-MS m/z 179 (M+H).

Using General Procedure B: Reaction of8-amino-4-methoxy-5,6,7,8-tetrahydroquinoline (0.297 g, 1.67 mmol) and4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (0.371, 1.71 mmol)with NaBH(OAc)₃ (0.493 g, 2.33 mmol) in CH₂Cl₂ (8 mL) for 60 minutesfollowed by purification of the crude material by column chromatographyon silica gel (20:1 CH₂Cl—₂—CH₃OH) provided 0.345 g (54%) of2-[4-(4-Methoxy-5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dioneas an off-white solid.

Using the General Procedure for N-alkylation: A solution of2-[4-(4-Methoxy-5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(0.340 g, 0.90 mmol),1-tert-(butoxycarbonyl)-2-(chloromethyl)-benzimidazole (0.492 g, 1.84mmol), and N,N-diisopropylethylamine (0.48 mL, 2.76 mmol) in CH₃CN (9mL) was heated at 80° C. for 22 hours. Purification of the crudematerial by column chromatography on silica gel (20:1:1CH₂Cl₂—CH₃OH—NH₄OH) followed by radial chromatography on silica gel (2mm plate, 100:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided 133 mg (24%) of2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(4-methoxy-5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester a yellow solid.

To a solution of2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(4-methoxy-5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (0.133 g, 0.22 mmol) in ethanol (4 mL) was addedhydrazine monohydrate (0.20 mL, 4.12 mmol) and the resultant mixture wasstirred at room temperature overnight. The mixture was filtered throughfilter paper and concentrated. Purification of the crude material bycolumn chromatography on silica gel (10:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided56 mg (68%) of the free base of the title compound as a yellow oil.

Using General Procedure D: Conversion of the free base to thehydrobromide salt followed by reprecipitation of the intermediate solidfrom methanol/ether gave COMPOUND 100 (72 mg, 71%) as a tan solid. ¹HNMR (D₂O) δ 1.53 (br s, 4H), 1.64-1.74 (m, 1H), 1.86-1.98 (m, 1H),2.14-2.19 (m, 1H), 2.28-2.32 (m, 1H), 2.50-2.63 (m, 2H), 2.71-2.87 (m,4H), 4.09 (s, 3H), 4.31-4.40 (m, 2H), 4.48 (d, 1 H, J=16.8 Hz), 7.34 (d,1H, J=7.2 Hz), 7.56-7.61 (m, 2H), 7.76-7.80 (m, 2H), 8.49 (d, 1H, J=7.2Hz); 13C NMR (D₂O) δ 19.74, 20.00, 21.76, 25.03, 25.37, 39.51, 47.98,51.69, 58.09, 60.11, 107.55, 114.22, 126.91, 128.05, 130.98, 141.05,150.21, 151.88, 170.91; ES-MS m/z 380 (M+H). Anal. Calcd. forC₂₂H₂₉N₅O.3.2HBr.2.2H₂O: C, 38.97; H, 5.44; N, 10.335; Br, 37.71. Found:C, 39.08; H, 5.13; N, 10.46; Br, 37.57.

Example 101

COMPOUND 101: Preparation ofN¹-(1H-benzimidazol-2-ylmethyl)-N¹-(3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

A solution of 3-bromoquinoline (24.4 g, 117 mmol) in anhydrous DMF (250mL) was treated with sodium methoxide (12.7 g, 235 mmol) and stirred at140° C. for 40 hours. The reaction mixture was then concentrated underreduced pressure and diluted with ethyl acetate (300 mL) and water (60mL). The organic phase was separated, washed with brine (2×60 mL) anddried (MgSO₄), filtered, and concentrated under reduced pressure. Thisgave, after purification by column chromatography on silica gel (ethylacetate/hexane; 1:4), 3-methoxyquinoline as a pale yellow liquid (1.15g, 6%). ¹H NMR (CDCl₃) δ 3.95 (s, 3H), 7.38 (d, 1H, J=1.5 Hz), 7.54 (m,2H), 7.72 (d, 1H, J=7.5 Hz), 8.04 (d, 1H, J=7.5 Hz), 8.67 (d, 1H, J=1.5Hz).

A solution of 3-methoxyquinoline (1.15 g, 7.2 mmol) in TFA (24 mL) wasprepared and the reaction flask was purged with argon. Platinum oxide(82 mg, 0.36 mmol) was then added, and hydrogen gas was bubbled throughthe solution for 16 h at room temperature. The mixture was then cooledto 0° C., basisified to pH 12 with 15% aqueous sodium hydroxidesolution, and extracted with ethyl acetate (3×100 mL). The organic phasewas then dried (MgSO₄), filtered, and concentrated to yield3-methoxy-5,6,7,8-tetrahydroquinoline (0.88 g, 74%). ¹H NMR (CDCl₃) δ1.77 (m, 2H), 1.85 (m, 2H), 2.75 (t, 2H, J=6.0 Hz), 2.85 (t, 2H, J=6.0Hz), 3.81 (s, 3H), 6.88 (d, 1H, J=1.5 Hz), 8.07 (d, 1H, J=1.5 Hz).

50% Hydrogen peroxide (0.30 mL, 5.4 mmol, 1 equivalent) was added to asolution of 3-methoxy-5,6,7,8-tetrahydroquinoline (0.87 g, 5.3 mmol) inacetic acid (12 mL) and heated to 70° C. for 7h. A second equivalent of50% hydrogen peroxide (0.30 mL, 5.4 mmol) was then added and thesolution stirred another 16 h at 70° C. The solution was thenconcentrated under reduced pressure and chloroform (20 mL) and sodiumcarbonate (5 g) was added. The mixture was stirred for a short periodand the supernatant was decanted and the solids washed with chloroform(50 mL). The organic was then dried (Na₂SO₄), filtered, and concentratedunder reduced pressure to provide the N-oxide as a yellow crystallinesolid (0.67 g, 70%). ¹H NMR (CDCl₃) δ 1.76 (m, 2H), 1.86 (m, 2H), 2.74(t, 2H, J=6.0 Hz), 2.88 (t, 2H, J=6.0 Hz), 3.81 (s, 3H), 6.67 (d, 1H,J=1.5 Hz), 7.98 (d, 1H, J=1.5 Hz).

A solution of 3-methoxy-5,6,7,8-tetrahydroquinolinium oxide (0.67 g, 3.7mmol) in acetic anhydride (9 mL, 95 mmol) was heated to 90° C. for 18 hfollowed by concentration under reduced pressure. This provided therearranged 8-acetyl-3-methoxy-5,6,7,8-tetrahydroquinoline as a crudebrown oil (0.83 g, 100%) that was again used immediately in the nextreaction. ¹H NMR (CDCl₃) δ 1.83 (m, 2H), 2.09 (s, 3H), 2.11 (m, 2H),2.80 (m, 2H), 3.84 (s, 3H), 5.94 (t, 1H, J=4.5 Hz), 6.94 (d, 1H, J=1.5Hz),. 8.22 (d, 1H, J=1.5 Hz).

A solution of 8-acetyl-3-methoxy-5,6,7,8-tetrahydroquinoline (0.83 g,3.7 mmol) in anhydrous methanol (18 mL) was treated with potassiumcarbonate (1.03 g, 7.5 mmol) and stirred at room temperature for 16 h.The mixture was concentrated under reduced pressure and CH₂Cl₂ (30 mL)and water (15 ml) was added. The aqueous phase was then extracted withCH₂Cl₂ (2×30 mL) and the combined organic phases were dried (MgSO₄),filtered, and concentrated to yield, after column chromatography (1:3ethyl acetate/hexane),(3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)-alcohol as a pale yellowsolid (0.35 g, 51%). ¹H NMR (CDCl₃) δ 1.81 (m, 2H), 1.99 (m, 1H), 2.22(m, 1H), 2.77 (m, 2H), 3.83 (s, 3H), 4.69 (t, 1H, J=7.5 Hz), 6.92 (d,1H, J=3.0 Hz), 8.12 (d, 1H, J=3.0 Hz).

The alcohol from above (0.35 g, 1.9 mmol) was then dissolved inanhydrous CH₂Cl₂ (19 mL) and treated with manganese dioxide (1.67 g, 19mmol) for 18 h at room temperature. The black mixture was filteredthrough a celite pad and the filtrate concentrated under reducedpressure. This gave the desired3-methoxy-5,6,7,8-tetrahydroquinolin-8-one (0.23 g, 68%) which was usedin the next reaction unpurified. ¹H NMR (CDCl₃) δ 2.18 (m, 2H), 2.74 (t,2H, J=6.0 Hz), 2.99 (t, 2H, J=6.0 Hz), 3.90 (s, 3H), 7.00 (d, 1H, J=3.0Hz), 8.35 (d, 1H, J=4.0 Hz).

Using general procedure B from above,3-methoxy-5,6,7,8-tetrahydroquinolin-8-one (0.23 g, 1.3 mmol),(4-aminobutyl)-carbamic acid tert-butyl ester (0.27 g, 1.4 mmol) andsodium triacetoxyborohydride (0.55 g, 2.6 mmol) were stirred at roomtemperature in CH₂Cl₂ (7 mL) for 18 hours. This yielded, after work-upand column chromatography (3:97 MeOH/CH₂Cl₂ to 15:1:84MeOH/NH₄OH/CH₂Cl₂),[4-(3-methoxy-5,6,7,8-tetrahydroquinolin-8-ylamino)-butyl]-carbamic acidtert-butyl ester (0.38 g, 84%).

To a solution of the above secondary amine (0.15 g, 0.43 mmol),N-(t-butoxycarbonyl)-2-chloromethylbenzimidazole (0.18 g, 0.69 mmol),and potassium iodide (5 mg, 0.02 mmol) in anhydrous acetonitrile (4.3mL) was added diisopropylethylamine (0.15 mL, 0.9 mmol) and stirred at60° C. for 16 hours. The mixture was then concentrated under reducedpressure and the residue partitioned between CH₂Cl₂ (10 mL) and brine (5mL). The organic phase was separated and the aqueous phase was extractedwith CH₂Cl₂ (2×10 mL). The combined organic phases were then dried(Na₂SO₄), filtered, and concentrated under reduced pressure to give acrude residue that was purified by column chromatography with silica gel(1:99 MeOH/CH₂Cl₂) followed by a second column with silica gel(saturated NH₃/Et₂O). This gave2-{[(4-tert-butoxycarbonylaminobutyl)-(3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (98 mg, 39%). ¹H NMR (CDCl₃) δ 1.40 (s, 9H), 1.43(br m, 4H), 1.62 (m, 1H), 1.69 (s, 9H), 1.87-2.05 (m, 3H), 2.62-2.80 (m,4H), 3.01 (br, 2H), 3.75 (s, 3H), 4.16 (m, 1H), 4.44 (d, 1H, J=15.0 Hz),4.55 (d, 1H, J=15.0 Hz), 4.90 (br, 1H), 6.71 (d, 1H, J=3.0 Hz), 7.27 (m,2H), 7.70 (m, 1H), 7.79 (m, 1H), 8.08(d, 1H, J=3.0 Hz).

Using general procedure D: The above material (97 mg, 0.17 mmol) wasconverted to the hydrobromide salt to provide COMPOUND 101 (85 mg) as awhite solid. ¹H NMR (D₂O) δ 1.54 (br, 4H), 1.75 (m, 1H), 1.93 (m, 1H),2.15 (m, 1H), 2.33 (m, 1H), 2.56 (br, 1H), 2.80 (br m, 1H), 2.87 (br,2H), 2.96 (br d, 2H), 3.96 (s, 3H), 4.37 (d, 1H, J=17.1 Hz), 4.43 (m,1H), 4.50 (d, 1H, J=16.8 Hz), 7.60 (m, 2H), 7.79 (m, 2H), 7.93 (br, 1H),8.28 (d, 1H, J=2.1 Hz). ¹³C NMR (D₂O) δ 20.54 (2C), 25.08, 25.43, 28.01,39.54, 47.95, 51.73, 57.43, 60.13, 114.25 (2C), 126.95 (2C), 127.25,131.00, 131.96, 141.38, 143.54, 151.85, 157.19. ES-MS m/z 380 (M+H).Anal. Calcd. for C₂₂H₂₉N₅O.3.2HBr.1.7H₂O: C, 39.50; H, 5.36; N, 10.47;Br, 38.22. Found: C, 39.77; H, 5.27; N, 10.34; Br, 37.96.

Example 102

COMPOUND 102: Preparation ofN¹-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-N¹-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diaminehydrochloride salt

Preparation of2-{4-[(1-methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione

To a solution of(S)-2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(3.89 g, 11.1 mmol) in acetonitrile (111 ml) was added2-chloromethyl-1-methyl-1H-benzoimidazole (prepared by reaction ofN-methyl-ortho-phenylenediamine with chloroacetic acid according toliterature procedure Phillips, M. A. J Chem. Soc. 1928, 2393; Goker, H.;Kus, C. Arch. Pharm. (Weinheim) 1995, 328, 425-430) (2.42 g, 13.4 mmol),diisopropylethylamine (1.93 ml, 11.1 ml), and potassium iodide (0.18 g,1.11 ml). The mixture was stirred for 16 hours at 50° C. The mixture wasconcentrated, redissolved in methylene chloride (200 ml) and dilutedwith saturated NaCl (400 ml). The reaction was extracted with methylenechloride (3×300 ml) and the combined organic extracts were dried(Na₂SO₄), filtered, and concentrated in vacuo to afford a dark red oil.Purification via column chromatography on silica gel (CH₂Cl₂:MeOH:NH₄OH,95:4:1, v/v/v) afforded the product as a light red foam (5.12 g, 77%).¹H NMR (CDCl₃) δ 1.63 (m, 8H), 2.65 (m, 4H), 3.54 (m, 2H), 4.10 (m, 6H),6.98 (dd, 1H, J=7.89, 4.38 Hz), 7.21 (m, 4H), 7.71 (m, 5H), 8.49 (d, 1H,J=3.95 Hz).

Preparation of N-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-N-(56,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

To a solution of the material from above (5.12 g, 10.37 mmol) in ethanol(75 ml) was added hydrazine hydrate (1.94 ml, 62.2 mmol). The solutionwas stirred for 16 hours at room temperature under a N₂ atmosphere. Awhite precipitate formed. Diethyl ether (75 ml) was added to the mixtureand the reaction was stirred for 10 min. The mixture was filtered andconcentrated. Purification via column chromatography on silica gel(CH₂Cl₂:MeOH:NH₄OH, 94:5:1, v/v/v) followed by a second purification bycolumn chromatography on silica gel (CH₂Cl₂:MeOH:NH₄OH, 94:5:1, v/v/v)afforded the product as a light yellow oil (2.63 g, 55%). ¹H NMR (CDCl₃)δ 1.39 (m, 5H), 1.99 (m, 3H), 2.63 (m, 6H), 3.48 (s, 2H), 3.97 (s, 3H),4.11 (m, 3H), 7.00 (dd, 1H, J=7.45, 4.38 Hz), 7.25 (m, 4H), 7.71 (d, 1H,J=7.45 Hz), 8.46 (d, 1H, J=4.38 Hz).

Preparation of COMPOUND 102:

To a solution ofN-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(2.63 g, 5.62 mmol) was added HCl-saturated methanol (11 ml) and themixture was stirred for 1 hour at room temperature under a N₂atmosphere. The solution was added dropwise to diethyl ether (1 L) toyield a chunky white precipitate. The white solid was isolated viasuction filtration under a steady stream of nitrogen, washed withdiethyl ether and dried at 40° C. in vacuo overnight (2.75 g, 91%). ¹HNMR (D₂O) δ 1.67 (m, 3H), 1.99 (m, 4H), 2.55 (m, 2H), 2.89 (m, 3H), 3.07(m, 2H), 3.31 (s, 1H), 4.07 (s, 3H), 4.43 (d, 1H, J=17.9 Hz), 4.69 (m,2H), 7.62 (m, 2H), 7.92 (m, 3H), 8.42 (d, 1H, J=7.89 Hz), 8.85 (d, 1H,J=5.7 Hz). ¹³C NMR δ (D₂O) 21.92, 26.65, 29.17, 32.42, 40.78, 53.61,61.82, 113.89, 115.76, 127.15, 127.89, 128.11, 131.79, 135.1, 141.38,141.91, 149.14, 152.75, 153.72. ES-MS m/z 364 (M+H). Anal. Calcd. ForC₂₂H₂₉N₅ 3.05HCl 0.06C₂H₄O₂ 3.07H₂O: C, 49.80; H 7.26; N, 13.13; Cl,20.24. Found. C, 49.80;, 7.25; N, 13.13; Cl, 20.24.

Example 103

COMPOUND 103: Preparation ofN¹-(1H-benzimidazol-2-ylmethyl)-N¹-(2-chloro-5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of methanesulfonic acid2-chloro-5,6,7,8-tetrahydro-quinolin-8-yl ester

To a solution of 2-chloro-8-hydroxy-5,6,7,8-tetrahydroquinoline(prepared as described by Zimmerman, S. C.; Zeng, Z.; Wu, W.; Reichert,D. E. J. Am. Chem. Soc. 1991, 113, 183-196) (700 mg, 3.81 mmol) inCH₂Cl₂ (19 mL), cooled to 0° C. under nitrogen, was added NEt₃ (0.80 mL,5.7 mmol) followed by MsCl (0.35 mL, 4.5 mmol). The solution was stirredat 0° C. for 40 minutes, then was diluted with saturated aqueous NaHCO₃(20 mL). The layers were separated and the aqueous solution wasextracted with CH₂Cl₂ (20 mL×2). The combined organic solution was dried(MgSO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography on silica (hexane/EtOAc, 2:1) gave themesylate as a white solid (904 mg, 3.45 mmol, 91%). ¹H NMR (CDCl₃) δ1.82-2.17 (m, 3H), 2.35-2.47 (m, 1H), 2.63-2.77 (m, 1H), 2.79-2.91 (m,1H), 3.29 (s, 3H), 5.62 (t, 1H, J=3.9 Hz), 7.23 (d, 1H, J=8.1 Hz), 7.45(d, 1H, J=8.1 Hz).

Preparation of 8-azido-2-chloro-5,6,7,8-tetrahydro-quinoline

A solution of the mesylate (886 mg, 3.39 mmol) and NaN₃ (285 mg, 4.38mmol) in DMF (10 mL) was stirred at 80° C. under nitrogen for 35minutes. Once cooled, the mixture was diluted with brine (20 mL) and wasextracted with EtOAc (20 mL×3). The combined organic solution was dried(MgSO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography on silica (hexane/EtOAc, 2:1) gave theazide as a pale yellow oil (679 mg, 3.25 mmol, 96%). ¹H NMR (CDCl₃) δ1.75-2.11 (m, 4H), 2.63-2.86 (m, 2H), 4.66 (t, 1H, J=4.2 Hz), 7.20 (d,1H, J=8.1 Hz), 7.42 (d, 1H, J=8.1 Hz).

Preparation of 8-amino-2-chloro-5,6,7,8-tetrahydro-quinoline

To a solution of the azide (351 mg, 1.68 mmol) in 10% H₂O in THF (10 mL)was added PPh₃ (867 mg, 3.31 mmol) and the reaction was stirred at roomtemperature for 18 hours. The solution was concentrated under reducedpressure and the residue was purified by flash column chromatography onsilica (CH₂Cl₂/MeOH, 9:1) giving the amine as a pale yellow oil (276 mg,1.51 mmol, 90%). ¹H NMR (CDCl₃) δ 1.62-1.83 (m, 2H), 1.86-2.03 (m, 3H),2.13-2.22 (m, 1H), 2.66-2.84 (m, 2H), 3.97 (dd, 1H, J=7.5, 5.4 Hz), 7.09(d, 1H, J=8.1 Hz), 7.33 (d, 1H, J=8.1 Hz).

Preparation of2-[4-(2-chloro-5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione

A solution of the amine (269 mg, 1.47 mmol) and4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (266 mg, 1.22mmol) in CH₂Cl₂ (8 mL) was stirred at room temperature under nitrogenfor 30 minutes. NaBH(OAc)₃ (398 mg, 1.88 mmol) was then added in oneportion as a solid and the reaction was stirred for a further 15 hours.The mixture was washed with 1M NaOH (10 mL×2) and brine (10 mL), dried(Na₂SO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 49:1:0.25)gave the secondary amine as a colourless oil (289 mg, 0.75 mmol, 62%).¹H NMR (CDCl₃) δ 1.55-1.81 (m, 6H), 1.93-2.03 (m, 1H), 2.06-2.14 (m,1H), 2.26 (br. s, 1H), 2.73 (t, 4H, J=7.1 Hz), 3.72 (t, 3H, J=6.9 Hz),7.07 (d, 1H, J=8.1 Hz), 7.32 (d, 1H, J=8.1 Hz), 7.69 (dd, 2H, J=5.4, 3.0Hz), 7.83 (dd, 2H, J=5.3, 3.0 Hz).

Preparation of 2-({(2-chloro-5 6,7,8-tetrahydro-quinolin-8-yl)-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-amino}-methyl)-benzimidazole-1-carboxylicacid tert-butyl ester

A solution of the amine (274 mg, 0.72 mmol),2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (227 mg,0.85 mmol), DIPEA (0.18 mL, 1.0 mmol) and KI (24 mg, 0.14 mmol) in CH₃CN(5 mL) was stirred at 60° C. under nitrogen for 17 hours. Once cooled toroom temperature, the solution was diluted with saturated aqueous NaHCO₃(10 mL) and extracted with CH₂Cl₂ (20 mL×3). The combined organicsolution was dried (MgSO₄), filtered and concentrated under reducedpressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH, 19:1) gave the tertiary amine as an off-white foam (435mg, 0.71 mmol, 99%). ¹H NMR (CDCl₃) δ 1.28-1.41 (m, 2H), 1.50-1.61 (m,2H), 1.64-1.76 (m, 10H), 1.80-1.91 (m, 1H), 1.93-2.05 (m, 1H), 2.09-2.22(m, 1H), 2.54-2.89 (m, 4H), 3.53 (t, 2H, J=7.2 Hz), 4.18 (dd, 1H, J=9.8,6.2 Hz), 4.49 (d, 1H, J=15.6 Hz), 4.74 (d, 1H, J=15.6 Hz), 6.93 (d, 1H,J=8.1 Hz), 7.19 (d, 1H, J=8.1 Hz), 7.22-7.26 (m, 2H), 7.63-7.71 (m, 3H),7.74-7.85 (m, 3H).

Preparation ofN¹-(1H-benzimidazol-2-ylmethyl)-N¹-(2-chloro-5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

A solution of the amine (212 mg, 0.345 mmol) and hydrazine monohydrate(0.20 mL, 4.1 mmol) in EtOH was stirred at reflux under nitrogen for 75minutes. The excess solvent was removed under reduced pressure, theresidue was taken up into saturated aqueous NaHCO₃ (10 mL) and wasextracted with CH₂Cl₂ (20 mL×3). The combined organic solution was dried(MgSO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 9:1:0.05)gave the primary amine as a white foam (99.9 mg, 0.260 mmol, 75%). ¹HNMR (CDCl₃) δ 1.29-1.52 (m, 4H), 1.61-1.77 (m, 1H), 1.79-1.94 (m, 1H),1.99-2.11 (m, 1H), 2.18-2.30 (m, 1H), 2.47-2.62 (m, 3H), 2.65-2.88 (m,3H), 3.94-4.09 (m, 3H), 7.15 (d, 1H, J=8.1 Hz), 7.19-7.23 (m, 2H), 7.38(d, 1H, J=8.1 Hz), 7.60-7.64 (m, 2H).

Preparation of COMPOUND 103:

To a solution of the amine (99.9 mg, 0.260 mmol) in glacial HOAc (1.5mL) was added a saturated solution of HBr in HOAc (0.5 mL). The solutionwas stirred at room temperature for 30 minutes, then Et₂O (5 mL) wasadded. The solvent was removed by pipette, the precipitate was washedwith Et₂O (2 mL×2) and was then dissolved into MeOH (2 mL). The mixturewas stirred for about 5 minutes and the product was re-precipitated bythe addition of Et₂O (5 mL). The solvent was again removed by pipetteand the precipitate was washed with Et₂O (2 mL×3). The product was driedunder reduced pressure, giving COMPOUND 103 as a fine, off-white powder(156 mg, 0.240 mmol, 92%). ¹H NMR (D₂O) δ 1.67-2.00 (m, 5H), 2.12-2.32(m, 2H), 2.39-2.52 (m, 1H), 2.67-2.82 (m, 2H), 3.03 (t, 2H, J=7.4 Hz),3.40-3.56 (m, 2H), 4.80-4.89 (m, 3H), 6.96 (d, 1H, J=8.1 Hz), 7.35 (d,1H, J=8.1 Hz), 7.51-7.55 (m, 2H), 7.68-7.71 (m, 2H). ¹³C NMR (D₂O) δ20.3, 21.1, 23.2, 24.6, 27.0, 39.3, 46.6, 54.1, 63.2, 114.9, 124.2,126.9, 132.6, 134.5, 141.7, 144.4, 147.9, 150.2. ES-MS m/z 384 (M+H),386 (M+2+H). Anal. Calcd. for C₂₁H₂₆ClN₅.3.1HBr.0.2C₄H₁₀O: C, 40.31; H,4.83; N, 10.78; Br 38.13. Found: C, 40.20; H, 4.91; N, 10.73; Br 38.44.

Example 105

COMPOUND 105:N¹-(1H-Benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydroquinoxalin-5-yl)-butane-1,4-diaminePreparation of 5-bromo-5,6,7,8-tetrahydroquinoxaline

To a solution of commercially available 5,6,7,8-tetrahydroquinoxaline(3.08 g, 23.0 mmol) in CCl₄ (200 mL) was added N-bromosuccinamide (4.09g, 23.0 mmol) and a catalytic amount (56 mg) of benzoyl peroxide. Thereaction mixture was heated at reflux for 17 hours. Saturated sodiumbicarbonate solution was added (100 mL), the layers were separated andthe aqueous phase was extracted with CH₂Cl₂ (2×200 mL). The organicextracts were dried and concentrated. The crude material contained 1:3:1ratio (GC) of starting material, mono- and dibromo products which wereseparated by column chromatography on silica gel using a mixture of 1:1EtOAc:hexanes to give 5-bromo-5,6,7,8-tetrahydroquinoxaline (3.03 g,54%) as a brown liquid: ¹H NMR (CDCl₃): δ 1.99-2.03 (m, 1H), 2.20-2.49(m, 3H), 2.97-3.10 (m, 1H), 3.11-3.20 (m, 1H), 5.48 (t, 1H, J=1.5 Hz),8.40 (s, 2H). It should be noted that this material is unstable whenexposed to air over 2-3 days and was used immediately in the nextreaction.

Preparation of 5-azido-5,6,7,8-tetrahydroquinoxaline

5-bromo-5,6,7,8-tetrahydroquinoxaline (2.75 g, 12.9 mmol) and sodiumazide (1.68 g, 25.8 mmol) were dissolved in DMF (50 mL) under nitrogenatmosphere and the reaction mixture was warmed to 60° C. for 2 days. Themixture was cooled to room temperature and poured over water (500 mL),and was extracted with CH₂Cl₂ (3×300 mL). The organic extracts werewashed with brine (2×200 mL), dried and concentrated in vacuo. The crudematerial was purified by flash column chromatography on silica gel using1:1 EtOAc/hexanes to afford 2.19 g (97%) of5-azido-5,6,7,8-tetrahydroquinoxaline as a yellow liquid: ¹H NMR(CDCl₃): δ 1.80-1.96 (m, 1H), 2.00-2.10 (m, 3H), 2.75-3.06 (m, 2H), 4.74(t, 1H, J=6.5 Hz), 8.44 (d, 1H, J=3 Hz), 8.45 (d, 1H, J=3 Hz); ¹³C NMR(CDCl₃): δ 18.6, 28.9, 31.7, 60.2, 142.6, 144.3, 150.3, 153.6.

Preparation of 5,6,7,8-tetrahydroquinoxalin-5-ylamine

A Parr shaker flask was charged with5-azido-5,6,7,8-tetrahydroquinoxaline (1.81 g, 10.33 mmol) and 10%palladium on carbon (10 wt % of Pd/C; 0.18 g). The reaction vessel wasevacuated and filled with nitrogen. Methanol (30 mL) was added and thereaction was hydrogenated at 30 psi for 40 minutes. The reaction mixturewas flushed with nitrogen and filtered through a plug of Celite® toprovide 5,6,7,8-tetrahydroquinoxalin-5-ylamine as an orange liquid (1.54g, 99%), which would rapidly turn dark brown. It was stored under anargon atmosphere at −20° C. ¹H NMR (CDCl₃): δ 1.62-1.79 (m, 1H),1.80-2.18 (m, 4H), 2.18-2.30 (m, 1H), 2.91-3.01 (m, 2H), 4.07 (dd, 1H,J=8.4, 5.4 Hz), 8.32-8.38 (m, 2H); ¹³C NMR (CDCl₃): δ 19.7, 31.7, 32.2,51.5, 142.0, 142.5, 152.6, 155.4; MS m/z: 150 (M+H⁺), 133.

Preparation of2-[4-(5,6,7,8-tetrahydro-quinoxalin-5-ylamino)-butyl]-isoindole-1,3-dione

To a solution of 5,6,7,8-tetrahydroquinoxalin-5-ylamine (313 mg, 2.09mmol) in CH₂Cl₂ (20 mL) at room temperature under inert atmosphere wasadded 4-(1,3,-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (227.8 mg,1.05 mmol) followed by sodium triacetoxyborohydride (444 mg, 2.10 mmol).The reaction mixture was stirred at room temperature for 2 hours.Saturated sodium bicarbonate solution (10 mL) was added and the mixturewas extracted with dichloromethane (3×20 mL). The combined organicextracts were washed with brine, dried (MgSO₄), filtered andconcentrated. The resultant material was purified by columnchromatography on silica gel (10:1:0.5 CH₂Cl₂:MeOH:NH₄OH) to provide theproduct as a clear oil (298 mg, 81%): ¹H NMR (CDCl₃): δ 1.56-1.66 (m,2H), 1.70-1.95 (m, 4H), 2.04-2.22 (m, 4H), 2.71-2.85 (m, 2H), 2.87-3.05(m, 2H), 7.69-7.73 (m, 2H), 7.80-7.85 (m, 2H), 8.34 (br s, 2H).

Preparation of2-{[[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(5,6,7,8-tetrahydroquinoxalin-5-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester

To a solution of2-[4-(5,6,7,8-tetrahydro-quinoxalin-5-ylamino)-butyl]-isoindole-1,3-dione(298 mg, 0.850 mmol) in CH₃CN (12 mL) was added2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (295mg, 1.11 mmol), potassium iodide (14 mg), and diisopropylethylamine(0.296 ml, 1.70 mmol). The reaction mixture was stirred at 60° C. for 17hours. Saturated sodium bicarbonate (15 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×30 mL). The combined organic extracts weredried (MgSO₄), filtered and concentrated. Purification of the crudematerial by column chromatography on silica gel (1:10 EtOAc:hexanes thenEtOAc then 1:10 MeOH:EtOAc) provided the product as a clear oil (422 mg,85%): ¹H NMR (CDCl₃): δ 1.34-1.43 (m, 2H), 1.48-1.60 (m, 2H), 1.68 (s,9H), 1.71-1.81 (m, 1H), 1.88-1.97 (m, 1H), 2.00-2.21 (m, 2H), 2.60-2.69(m, 1H), 2.76-2.93 (m, 3H), 3.55 (t, 2H, J=6.9 Hz), 4.29 (dd, 1H, J=9.6,5.4 Hz), 4.46 (d, 1H, J=15.3 Hz), 4.61 (d, 1H, J=15.3 Hz), 7.19-7.24 (m,2H), 7.63-7.69 (m, 3H), 7.74-7.81 (m, 3H), 8.18 (d, 1H, J=2.1 Hz), 8.27(d, 1H, J=2.1 Hz).

Preparation ofN¹-(1H-Benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydroquinoxalin-5-yl)-butane-1,4-diamine(COMPOUND 105)

To a solution of2-{[[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(5,6,7,8-tetrahydroquinoxalin-5-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (420 mg, 0.723 mmol) in ethanol (20 mL) at roomtemperature was added hydrazine hydrate (0.20 mL). The mixture wasstirred for 17 hours. The mixture was concentrated in vaccuo and theresultant material was purified by column chromatography on silica gel(1:1:10 MeOH:NH₄OH:CH₂Cl₂) to provide COMPOUND 105 as a colourless foam(161 mg, 64%): ¹H NMR (CDCl₃) δ 1.37-1.48 (m, 5H), 1.70-1.79 (m, 1H),1.81-1.97 (m, 1H), 2.07-2.16 (m, 1H), 2.18-2.31 (m, 1H), 2.49-2.59 (m,4H), 2.71-2.78 (m, 1H), 2.90-3.08 (m, 2H), 3.98 (d, 1H, J=16.5 Hz), 4.07(d, 1 H, J=16.5 Hz), 4.06-4.12 (m, 1H), 7.18-7.21 (m, 2H), 7.57-7.59 (m,2H), 8.41 (s, 1H), 8.54 (s, 1H); ¹³C NMR (CDCl₃) δ 21.2, 22.9, 26.3,30.5, 32.6, 41.7, 49.8, 51.4, 62.0, 122.3, 142.1, 143.3, 153.8, 155.4,155.5; ES-MS m/z 351 (M+H). Anal. Calcd. for C₂₀H₂₆N₆.0.3CH₂Cl₂.0.2H₂O:C, 64.24; H, 7.17; N, 22.14. Found: C, 64.16; H, 7.41; N, 22.15.

Example 106

COMPOUND 106: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-butane-1,4-diamine(hydrobromide)

To a solution of triphenylphosphine (10.9 g, 41.5 mmol), 3-buten-ol(2.49 g, 34.6 mmol) and 2-bromo-3-pyridinol (6.01 g, 34.6 mmol) in THF(200 mL) at 0° C. was added diisopropyl azodicarboxylate (7.49 mL, 38.0mmol) very slowly. Ice bath was removed after addition of diisopropylazodicarboxylate and the mixture was allowed to stir at 50° C. for 20hours under argon. The reaction mixture was diluted with EtOAc (300 mL),and washed with sat. NaHCO₃ (2×150 mL), brine (2×150 mL) and dried overNa₂SO₄. Evaporation of the solvent and purification of the residue byflash chromatography on silica gel (Hexanes/EtOAc, 90:10 followed by85:15) afforded 2-bromo-3-but-3-enyloxy-pyridine (7.04 g, 89%) as acolourless oil. ¹H NMR (CDCl₃) δ 2.58-2.66 (m, 2H), 4.08 (t, 2H, J=6.9Hz), 5.13-5.24 (m, 2H), 5.87 -5.98 (m, 1H), 7.10 -7.14 (m, 1H), 7.18-7.22 (m, 1H), 7.97 (dd, 1H, J=6.0, 1.5 Hz).

An anhydrous DMF solution (120 mL) of 2-bromo-3-but-3-enyloxy-pyridine(6.43 g, 28.2 mmol) in a round bottom schlenk flask was degassed withargon using the freeze/pump/thaw method. To this freshly degassedsolution was added triphenylphosphine (2.66 g, 10.2 mmol), palladiumacetate (696 mg, 3.10 mmol), potassium acetate (13.84 g, 141 mmol), andtetraethylammoniumchloride hydrate (9.35 g, 56.4 mmol). The resultantmixture was heated at 110° C. under argon for 18 hours. The reactionmixture was cooled to room temperature and diluted with EtOAc (300 mL),brine (120 mL) and H₂O (60 mL). The organic phase was separated andwashed with brine (3×120 mL) and dried over Na₂SO₄. Evaporation of thesolvent and purification of the residue by flash chromatograph on silicagel (Hexanes/EtOAc, 95:5) afforded4-methylene-3,4-dihydro-2H-pyrano[3,2-b]pyridine (2.8 g, 67%) as a whitesolid. ¹H NMR (CDCl₃) δ 2.79 -2.86 (m, 2H), 4.25 (t, 2H, J=5.7 Hz), 5.08(d, 1H, J=1.6 Hz), 6.19 (d, 1H, J=1.6 Hz), 7.08-7.17 (m, 2H), 8.20 (dd,1H, J=4.7, 1.6 Hz).

To a solution of 4-methylene-3,4-dihydro-2H-pyrano[3,2-b]pyridine (2.77g, 18.8 mmol) and 4-methylmorpholine N-oxide (6.61 g, 56.5 mmol) inCH₂Cl₂ (45 mL) was added osmium tetroxide (2.5 wt. % solution in2-methyl-2-propanol, 6.8 mL, 0.68 mmol). The resultant mixture wasstirred at room temperature under N₂ for 80 hours, diluted with EtOAc(300 mL), and then filtered through a pad of celite. Evaporation of thesolvent and purification of the residue by flash chromatograph on silicagel (CH₂Cl₂/MeOH/NH₄OH, 95:4:1) afforded the4-hydroxymethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridinyl-4-ol (2.13 g, 62%)as a yellow solid.

To a solution of4-hydroxymethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridinyl-4-ol (2.13 g, 11.8mmol) in H₂O (15 mL) was added sodium periodate (5.03 g, 23.5 mmol) andthe mixture was allowed to stir at room temperature for 2 hours. Themixture was diluted with EtOAc (100 mL) and H₂O (20 mL) and stirredvigorously for 10 minutes. The aqueous phase was separated and extractedwith CH₂Cl₂ (2×50 mL). The combined organic extracts were dried(Na₂SO₄), filtered and concentrated. Purification of the residue byflash chromatograph on silica gel (Hexanes/EtOAc, 60:40 followed by0:100) gave 2,3-Dihydro-pyrano[3,2-b]pyridin-4-one (1.28 g, 73%) as awhite solid. ¹H NMR (CDCl₃) δ 2.98 (t, 2H, J=6.6 Hz), 4.62 (t, 2H, J=6.6Hz), 7.36 -7.44 (m, 2H), 8.44 (dd, 1H, J=12.6, 2.1 Hz).

Reaction of 2,3-Dihydro-pyrano[3,2-b]pyridin-4-one (277 mg, 1.85 mmol)with (4-Amino-butyl)-carbamic acid tert-butyl ester (269 mg, 1.43 mmol)using general procedure B for reductive amination with NaBH(OAc)₃ (605mg, 2.86 mmol), followed by flash chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 97:2:1 followed by 95:4:1) afforded[4-(3,4-Dihydro-2H-pyrano[3,2-b]pyridin-4-ylamino)-butyl]-carbamic acidtert-butyl ester (330 mg, 72%) as a pale yellow oil.

To a solution of[4-(3,4-Dihydro-2H-pyrano[3,2-b]pyridin-4-ylamino)-butyl]-carbamic acidtert-butyl ester (329 mg, 1.02 mmol) in CH₃CN (5 mL) was addedN,N-diisopropylethylamine (0.28 mL, 1.63 mmol) followed by2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (328 mg,1.23 mmol) and potassium iodide (20 mg, 0.1 mmol). The resultant mixturewas heated to 60° C. for 16 hours then cooled to room temperature. Themixture was concentrated and the residue was partitioned between CH₂Cl₂(25 mL) and saturated aqueous NaHCO₃ (20 mL). The phases were separatedand the aqueous phase was extracted with CH₂Cl₂ (2×15 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered, and concentrated.Purification of the crude material by flash column chromatography onsilica gel (CH₂Cl₂/MeOH/NH₄OH, 95:4:1) provided2-{[(4-tert-Butoxycarbonylamino-butyl)-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (380 mg, 67%) as a white foam.

Using General Procedure D: Conversion of the white foam from above (107mg, 0.19 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave COMPOUND 106 (110 mg,90%) as a cream solid. ¹H NMR (D₂O) δ 1.43-1.66 (m, 4H), 2.38-2.50 (m,2H), 2.53-2.63 (m, 1H), 2.78-2.92 (m, 3H), 4.33-4.43 (m, 1H), 4.43 (d,1H, J=17.4 Hz), 4.55 (d, 1H, J=17.1 Hz), 4.64-4.78 (m, 2H), 7.57-7.63(m, 2H), 7.76-7.87 (m, 3H), 7.98 (dd, 1H, J=8.7, 0.9 Hz), 8.40 (dd, 1H,J=5.4, 0.9 Hz); ¹³C NMR (CDCl₃) δ 19.72, 24.98, 25.32, 39.52, 47.95,51.48, 56.53, 67.48, 114.28, 126.93, 127.55, 131.03, 134.75, 134.84,138.80, 151.75, 155.80; ES-MS m/z 352 (M+H). Anal. Calcd. forC₂₀H₂₅N₅O.3.1HBr.1.0 H₂O.0.2C₄H₁₀O: C, 39.34; H, 5.09; N, 11.03; Br,39.00. Found: C, 39.29; H, 4.92; N, 10.96; Br, 39.02.

Example 107

COMPOUND 107: Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(S)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl-butane-1,4-diamine(hydrochloride salt) Preparation of4-methylene-3,4-dihydro-2H-pyrano[3,2-b]pyridine

To a stirred 0° C. solution of 2-bromo-3-pyridinol (14.7 g, 84 mmol),3-buten-1-ol (7.25 mL, 84 mmol), and triphenylphosphine (26.5 g, 100mmol) in THF (420 mL) was added DIAD (18.3 mL, 93 mmol) over 5 min. Themixture was heated to 50° C. under a nitrogen atmosphere for 21 h,cooled to room temperature, and concentrated. The resultant brown oilwas dissolved in ethyl acetate (1 L), washed with saturated sodiumbicarbonate solution (2×500 mL), washed with brine (2×500 mL), driedover Na₂SO₄, and concentrated. Purification of the crude material bycolumn chromatography over silica gel (5:1 hexanes/EtOAc) provided thedesired bromide (20.2 g, 100%) as a yellow oil.

A solution of the bromide (19.2 g, 84 mmol) from above in anhydrous DMF(170 mL) was frozen under an argon atmosphere, and thawed while underhigh vacuum to degas the solution. This freeze-thaw cycle was repeatedfour times. A pressure-flask was purged with argon and charged withtriphenylphosphine 7.96 g, 30 mmol), potassium acetate (41.4 g, 420mmol), tetraethylammonium chloride hydrate (27.9 g, 170 mmol), palladium(II) acetate (2.08 g, 9.3 mmol), and the degassed solution from above.The flask was evacuated and back-filled with argon four times, sealed,and heated to 110° C. with stirring for 39 h. The mixture was cooled toroom temperature, diluted with ethyl acetate (1 L) and stirred with amixture of brine (500 mL) and water (200 mL) for 30 min. The layers wereseparated and the organic layer was washed with saturated sodiumbicarbonate solution (500 mL) and brine (3×500 mL). The organic layerwas dried over Na₂SO₄, concentrated, and dried under high vacuum for 1h. Purification of the crude material (25 g) by column chromatography onsilica gel (200:1 CH₂Cl₂/MeOH) provided the title compound (5.9 g, 47%)as a yellow oil. ¹H NMR (CDCl₃) δ 2.80-2.85 (m, 2H), 4.25 (t, 2H, J=5.7Hz), 5.08 (s, 1H), 6.20 (s, 1H), 7.08-7.17 (m, 2H), 8.20 (dd, 1H, J=4.0,1.8 Hz).

Preparation of (S)-(3,4-Dihydro-2H-pyrano[3,2-b]pyridin-4-yl)amine

A solution of 4-methylene-3,4-dihydro-2H-pyrano[3,2-b]pyridine (5.9 g,40 mmol), 4-methylmorpholine-N-oxide (14.0 g, 120 mmol), and osmiumtetroxide (15.4 mL, 2.5 wt % in tert-butanol, 1.2 mmol) indichloromethane (100 mL) was stirred at room temperature under anitrogen atmosphere for 7 days. The mixture was diluted with diethylether (100 mL), filtered through diatomaceous earth, and concentrated.Purification of the crude material by column chromatography over silicagel (25:1 CH₂Cl₂/MeOH) provided the diol (4.5 g, 62%) as a brown oil.

To a stirred solution of the diol (4.5 g, 25 mmol) from above indeionized water (100 mL) was carefully added sodium periodate (10.7 g,50 mmol)—exothermic—and stirring was continued for 1.5 h. The mixturewas diluted with ethyl acetate (200 mL), stirred for 2 h, and the layerswere separated. The aqueous layer was extracted with dichloromethane(2×50 mL). The organic layers were combined, dried over Na₂SO₄, andconcentrated to give the desired ketone (2.9 g, 78%) as an off-whitesolid.

A solution of the ketone (2.9 g, 19 mmol) from above and hydroxylaminehydrochloride (1.6 g, 23 mmol) in methanol (100 mL) was stirred at roomtemperature for 1 h. Saturated sodium bicarbonate solution (80 mL) wasadded and the mixture was concentrated on a rotary evaporator to removethe methanol. The resultant mixture was extracted with dichloromethane(1×200 mL, 3×75 mL) and 9:1 CHCl₃/MeOH (5×200 mL). The organic layerswere combined, dried over Na₂SO₄, and concentrated to give the oxime(3.0 g, 94%) as a brown solid.

Zinc dust was added slowly to a stirred 0° C. suspension of oxime (3.0g, 18 mmol) from above, ammonium acetate (1.6 g, 20 mmol), ammoniumhydroxide (85 mL), and ethanol (16 mL). The cooling bath was removed andstirring was continued for 2.5 h. The slurry was filtered through celiteand the filtrate was extracted with dichloromethane (3×150 mL). Theorganic extracts were combined, dried over MgSO₄, concentrated, anddried under high vacuum to provide the racemic amine (2.6 g, 94%).

A stirred slurry of the amine (2.6 g, 17 mmol) and CAL (0.80 g) in ethylacetate (65 mL) was heated to 40° C. for 3 h. The mixture was cooled toroom temperature, filtered, and concentrated. Purification of the crudematerial by column chromatography on silica (20:1 CH₂Cl₂/MeOH, then20:1:1 CH₂Cl₂/MeOH/NH₄OH) afforded the title compound (1.14 g, 88%) as ared-brown oil. ¹H NMR (CDCl₃) δ 1.90-2.02 (m, 1H), 2.24-2.35 (m, 1H),4.13 (t, 1H, J=6.4 Hz), 4.18-4.36 (m, 2H), 7.06-7.13 (m, 2H), 8.17 (dd,1H, J=3.9, 2.2 Hz).

Preparation ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(S)-3,4-dihydo-2H-pyrano[3,2-b]pyridin-4-yl-butane-1,4-diaminehydrochloride salt (COMPOUND 107)

A slurry of (S)-(3,4-Dihydro-2H-pyrano[3,2-b]pyridin-4-yl)amine (1.14 g,7.6 mmol) from above,4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (1.57 g, 7.2mmol), and potassium carbonate (1.00 g, 7.2 mmol) in THF (15 mL) wasstirred at room temperature for 1 h. The mixture was filtered through aglass-fritted funnel and the filter cake was washed with THF (15 mL).The combined filtrate was treated with sodium triacetoxyborohydride (4.7g, 22 mmol) and the mixture was stirred for 1 h. The reaction wasquenched with saturated sodium bicarbonate solution (150 mL) and stirredfor 15 min. The layers were separated and the aqueous layer wasextracted with dichloromethane (3×75 mL). The combined organic layerswere dried over Na₂SO₄ and concentrated. Purification of the crude brownoil by column chromatography on silica gel (EtOAc) gave the desiredsecondary amine (2.25 g, 89%) as a white solid.

A slurry of the amine (2.25 g, 6.4 mmol) from above,N-boc-2-chloromethyl-benzimidazole (1.87 g, 7.0 mmol),diisopropylethylamine (1.8 mL, 10 mmol), potassium iodide (50 mg, 0.3mmol), and acetonitrile (65 mL) was stirred at 50° C. under a nitrogenatmosphere for 40 h. The mixture was cooled to room temperature andconcentrated. The resultant residue was dissolved in dichloromethane (75mL), washed with saturated sodium bicarbonate solution (3×50 mL), andwashed with brine (50 mL). The organic layer was dried over Na₂SO₄ andconcentrated. Purification of the crude material by repetitive columnchromatography on silica (first column: EtOAc, second column: 30:1CH₂Cl₂/MeOH) provided the desired protected amine (2.97 g, 80%) as apale yellow foamy solid.

To a stirred solution of the protected amine (2.97 g, 5.1 mmol) fromabove in ethanol (50 mL) was added hydrazine hydrate (2.5 mL, 50 mmol)and stirring was continued at room temperature for 66 h. The mixture wasdiluted with diethyl ether (50 mL). The resultant white slurry wasfiltered and concentrated. Purification of the crude material by columnchromatography on silica gel (20:1:1 CH₂Cl₂/MeOH/NH₄OH) gave the desiredamine (1.80 g, 100%) as a white foamy solid.

Following General Procedure D: Conversion of the free base (1.80 g, 5.1mmol) from above to the hydrochloride salt gave COMPOUND 107 (2.14 g,82%) as a white solid. ¹H NMR (D₂O) δ 1.49-1.60 (m, 4H), 2.39-2.49 (m,2H), 2.52-2.63 (m, 1H), 2.78-2.91 (m, 3H), 4.32-4.42 (m, 1H), 4.48 (q,2H, J=17.2 Hz), 4.65-4.72 (m, 2H), 7.56-7.7.63 (m, 2H), 7.76-7.85 (m,3H), 7.97 (dd, 1H, J=8.7, 1.2 Hz), 8.39 (dd, 1H, J=5.7, 1.2 Hz); ¹³C NMR(D₂O) δ 19.74, 24.95, 25.27, 39.48, 47.87, 51.46, 56.51, 67.41,114.25(2), 126.92(2), 127.50, 131.04, 134.66, 134.82, 138.84, 151.77,155.74; ES-MS m/z 352 (M+H). Anal. Calcd. forC₂₀H₂₅N₅O.3.0HCl.2.5H₂O.0.1(C₂H₅)₂O: C, 47.74; H, 6.68; N, 13.64; Cl,20.72. Found: C, 47.74; H, 6.94; N, 13.33; Cl, 20.75.

The enantiomeric purity of COMPOUND 107 was determined to be 100% ee bychiral HPLC using the following conditions: Instrument: Hewlett Packard1100 HPLC (VWD1); Column: ChiralCel OD, 0.46 cm×25 cm; Mobile Phases: A:90:5:5 hexanes/reagent alcohol/methanol with 0.1% DEA, B: hexanes;Isocratic: 80% A, 20% B; Total Run Time: 25 min; Flow Rate: 1.0 mL/min;Temperature: 40° C.; Detector: UV @ 270 nm; Injection volume: 10 μL.

Retention time of the S enantiomer=12.0 min.

Retention time of the R enantiomer=15.2 min.

Example 108

COMPOUND 108:N¹-(1H-Benzoimidazol-2-ylmethyl)-N¹-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation ofN-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide

To a 3-neck, 500 mL round bottom flask containing a stir bar was added2-methyl-8-acetamidoquinoline (5.69 g, 28.4 mmol) and platinum(IV) oxide(322 mg, 5 mol %). The flask was equipped with two Teflon cannulae: onefor purging of the reaction flask with nitrogen gas and introduction ofhydrogen, and the other leading to a flask connected to a bubbler.Trifluoroacetic acid (100 mL) was added to the reaction flask under anatmosphere of nitrogen. The stirred reaction mixture was flushed withnitrogen gas and warmed to 60° C. Hydrogen gas was bubbled through thestirred reaction for 3 h. The progress of the reaction was monitored byGC and/or TLC. The reaction mixture was cooled to room temperature,purged with nitrogen gas and the catalyst was filtered through a pad ofCelite and washed with CH₂Cl₂ (100 mL). The solvent was removed in vacuoand the residue was basified with saturated NaOH (pH>14). The mixturewas then extracted with CHCl₃ (3×250 mL). The organic extracts weredried (MgSO₄), filtered and concentrated. The crude material waspurified by flash chromatography using 10% MeOH in EtOAc to provide theproduct (3.83 g, 66%) as a white solid. ¹H NMR δ 1.57-1.66 (m, 1H),1.77-1.86 (m, 2H), 2.02 (s, 3H), 2.44 (s, 3H), 2.43-2.57 (m, 1H),2.68-2.73 (m, 2H), 4.67-4.74 (m, 1H), 6.79 (br s, 1H), 6.92 (d, 1H, J=8Hz), 7.24 (d, 1H, J=8 Hz); ¹³C NMR δ 21.6, 25.4, 25.8, 29.6, 31.0, 53.0,123.4, 131.4, 139.2, 155.9, 157.2, 172.2; ES-MS m/z: 227 (M+Na⁺).

Preparation of 2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamine

N-(2-Methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide (4.51 g, 22.1mmol) was dissolved in 6 N HCl (40 mL). The mixture was heated at refluxfor 17 h. The reaction mixture was cooled to room temperature, basifiedwith saturated NaOH (pH>14) and extracted with chloroform (5×100 mL).The organic extracts were dried (MgSO₄) and concentrated. The crudematerial was purified by distillation (bp 102-104° C. at 0.20 mm Hg) toyield the product as a clear liquid (3.25 g, 99%). ¹H NMR (CDCl₃, 300MHz) δ 1.62-1.82 (m, 2H), 1.84-2.00 (m, 3H), 2.11-2.20 (m, 1H), 2.49 (s,3H), 2.61-2.82 (m, 2H), 3.93-4.00 (m, 1H), 6.91 (d, 1H), J=7.8 Hz), 7.25(d, 1H, J=7.8 Hz); ¹³C NMR (CDCl₃) δ 20.4, 24.6, 29.1, 32.6, 51.8,121.7, 128.6, 137.6, 155.9, 159.0; ES-MS m/z: 163 (M+H⁺), 146 (M-NH₂).

Preparation of2-[4-(2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamino)-butyl]-isoindole-1,3-dione

To a solution of 2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamine (237 mg,1.46 mmol) in CH₂Cl₂ (20 mL) at room temperature under inert atmospherewas added 4-(1,3,-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (159mg, 0.731 mmol) followed by sodium triacetoxyborohydride (309 mg, 2.92mmol). The reaction mixture was stirred at room temperature for 2 hours.Saturated sodium bicarbonate solution (10 mL) was added and the mixturewas extracted with dichloromethane (3×20 mL). The combined organicextracts were washed with brine, dried (MgSO₄), filtered andconcentrated. The resultant material was purified by columnchromatography on silica gel (10:1:0.5 CH₂Cl₂: MeOH: NH₄OH) to providethe product as a yellow oil (210 mg, 79%): ¹H NMR (CDCl₃): δ 1.56-1.83(m, 6H), 1.90-2.04 (m, 2H), 2.04-2.18 (m, 2H), 2.47 (s, 3H), 2.64-2.80(m, 4H), 3.70-3.76 (m, 3H), 6.90 (d, 1H, J=7.8 Hz), 7.24 (d, 1H, J=7.8Hz), 7.69-7.73 (m, 2H), 7.81-7.85 (m, 2H).

Preparation of2-{[[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester

To a solution of2-[4-(2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamino)-butyl]-isoindole-1,3-dione(210 mg, 0.578 mmol) in CH₃CN (12 mL) was added2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (200mg, 0.751 mmol), potassium iodide (14 mg), and diisopropylethylamine(0.201 ml, 1.16 mmol). The reaction mixture was stirred at 60° C. for 17hours. Saturated sodium bicarbonate (15 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×30 mL). The combined organic extracts weredried (MgSO₄), filtered and concentrated. Purification of the crudematerial by column chromatography on silica gel (1:10 EtOAc:hexanes thenEtOAc then 1:10 MeOH:EtOAc) provided the product as a clear oil (228 mg,66%): ¹H NMR (CDCl₃): δ 1.23-1.31 (m, 2H), 1.46-1.58 (m, 2H), 1.63-1.73(m, 1H), 1.68 (s, 9H), 1.73-1.85 (m, 1H), 1.89-1.98 (m, 1H), 2.10-2.18(m, 1H), 2.40 (s, 3H), 2.60-2.83 (m, 5H), 3.50 (t, 2H, J=7.2 Hz), 4.20(dd, 1H, J=9.6, 6.0 Hz), 4.50 (d, 1H, J=15.6 Hz), 4.72 (d, 1H, J=15.6Hz), 6.79 (d, 1H, J=7.5 Hz), 7.14 (d, 1H, J=7.5 Hz), 7.19-7.24 (m, 2H),7.63-7.69 (m, 3H), 7.74-7.81 (m, 3H).

Preparation ofN¹-(1H-Benzoimidazol-2-ylmethyl)-N¹-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine

To a solution of2-{[[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (228 mg, 0.384 mmol) in ethanol (10 mL) at roomtemperature was added hydrazine hydrate (0.10 mL). The mixture wasstirred for 4 days. The mixture was concentrated in vaccuo and theresultant material was purified by column chromatography on silica gel(1:1:10 MeOH: NH₄OH: CH₂Cl₂) to provide the product as a colourless oil(82 mg, 59%): ¹H NMR (CDCl₃) δ 1.25-1.45 (m, 4H), 1.60-1.70 (m, 1H),1.81-1.93 (m, 1H), 1.97-2.04 (m, 1H), 2.10-2.18 (m, 1H), 2.46-2.56 (m,3H), 2.62-2.82 (m, 6H), 3.95-3.99 (m, 1H), 4.00 (d, 1H, J=17.1 Hz), 4.09(d, 1H, J=17.1 Hz), 6.98 (d, 1H, J=7.8 Hz), 7.15-7.21 (m, 2H), 7.30 (d,1H, J=7.8 Hz), 7.57-7.60 (m, 2H).

Preparation ofN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) (COMPOUND 108)

To a solution ofN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine(82 mg, 0.23 mmol) in glacial acetic acid (0.5 mL) was added HBrsaturated acetic acid (1 mL). The reaction mixture was stirred for 10minutes, then diethyl ether was added (50 mL). The white precipitate wasallowed to settle and the solvent was removed with a pipette. Et₂O (50mL) was again added then decanted. The resulting precipitate wasdissolved in methanol (1.5 mL), ether was added (3×50 mL) then it wasremoved with a pipette. The resultant yellow powder was dried underreduced pressure to give 113 mg (76%) of the product: ¹H NMR (D₂O) δ1.48-1.63 (m, 4H), 1.65-1.78 (m, 1H), 1.82-2.01 (m, 1H), 2.02-2.15 (m,1H), 2.25-2.31 (m, 1H), 2.50-2.63 (m, 1H), 2.67-2.78 (m, 4H), 2.78-3.00(m, 4H), 4.39 (d, 1H, J=16.8 Hz), 4.49 (d, 1H, J=16.8 Hz), 7.52-7.64 (m,3H), 7.70-7.79 (m, 2H), 8.13 (d, 1H, J=7.8 Hz); ¹³C NMR (D₂O) δ 19.7,20.3, 20.5, 25.1, 27.4, 39.6, 47.7, 51.8, 60.1, 114.3, 126.9, 130.9,137.6, 147.8, 150.0, 151.7, 152.8; ES-MS m/z 365 (M+H). Anal. Calcd. forC₁₇H₂₂N₄.3.0HBr.2.3H₂O: C 40.80, H 5.70, N 10.81, Br 37.01. Found: C40.78, H 5.82, N 10.54, Br 37.09.

Example 110

COMPOUND 110:N1-(1H-Benzoimidazol-2-ylmethyl)-N1-(4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of 4,5,6,7-tetrahydorbenzoimidazol-4-one

Following a modified literature procedure (Helv. Chim. Acta 1979, 62,497), N₂O₄ was bubbled into a heterogeneous mixture of1,3-cyclohexanedione (6.98 g, 62.3 mmol) (recrystallized from benzene)in dry diethyl ether (500 mL) at 0° C. for about 10 minutes. The mixturewas warmed to room temperature and N₂O₄ was further bubbled until thereaction mixture became homogenous and orange in colour. The mixture wasstirred for 0.5 hr. Excess N₂O₄ was removed by bubbling argon gas andthe solvent was removed on rotorvap to provide a dark orange oil whichrapidly turned black.

Approximately half of this material was dissolved in glacial acetic acid(50 mL) in a Parr shaker flask. Freshly prepared formic acetic anhydride(50 mL) (prepared by mixing 50 mL of formic acid with 25 mL of aceticanhydride and stirring for 2 hours—J. Med. Chem. 2001, 44, 36-46) and ˜2g of palladium on carbon (10%) were added and the mixture washydrogenated at 50 psi for 2 hrs. The volatiles were removed on highvaccum rotorvap and the ¹H NMR of the crude material (5.2 g, black tar)contained a signal at δ 7.99 ppm (formylated amine product).

To the crude black oil was added 15 mL of formic acid and 60 mLformamide and the mixture was heated at 150° C. for 30 minutes. Thevolatiles were rotorvaped on high vacuum rotorvap (heated bath to 80°C.). Freshly prepared formic acetic anhydride (40 mL) and glacial aceticacid (20 mL) were added and the black mixture was heated at 100° C. for1 hr. The volatiles were again removed using hagh vacuum. Repeatedpurification of the material by flash column chromatography (4:1:0.2CH₂Cl₂:MeOH:NH₄OH) on silica gel provided4,5,6,7-tetrahydorbenzoimidazol-4-one (893 mg) contaminated withformamide and other impurities. ¹H NMR (CDCl₃): δ 2.02 (p, 2H, J=6.3Hz), 2.39 (t, 2H, J=6.3 Hz), 2.75 (t, 2H, J=6.3 Hz), 7.82 (s, 1H).

Preparation of 7-oxo-4,5,6,7-tetrahydorbenzoimidazole-1-carboxylic acidtert-butyl ester

This material (893 mg, 6.56 mmol) was treated with tert-butylanhydride(2.15 g, 9.84 mmol) in DMF (15 mL) and diisopropylethylamine (2.29 mL,13.0 mL) at room temperature for 17 hours. The residue was dissolved inMeOH and EtOAc and was left in the fridge for 3 days. The solid whichprecipitated (2 recrystallizations) was clean7-oxo-4,5,6,7-tetrahydorbenzoimidazole-1-carboxylic acid tert-butylester (759 mg, 5.5% from 1,3-cyclohexanedione). ¹H NMR (CDCl₃): δ 1.64(s, 9H), 2.21 (m, 2H), 2.56 (dd, 2H, J=6.6, 6.3 Hz), 3.14 (dd, 2H,J=6.3, 6.0 Hz), 8.05 (s, 1H).

Preparation of7-(4-tert-butoxycarbonylamino-butylamino)-4,5,6,7-tetrahydrobenzoimidazole-1-carboxylicacid tert-butyl ester

To a solution of 7-oxo-4,5,6,7-tetrahydorbenzoimidazole-1-carboxylicacid tert-butyl ester (632 mg, 2.82 mmol) in CH₂Cl₂ (50 mL) at roomtemperature under inert atmosphere was added (4-amino-butyl)carbamicacid tert-butyl ester (745 mg, 4.23 mmol) followed by sodiumtriacetoxyborohydride (896 mg, 4.23 mmol). The reaction mixture wasstirred at room temperature for 17 hours. Saturated sodium bicarbonatesolution (20 mL) was added and the mixture was extracted withdichloromethane (3×30 mL). The combined organic extracts were washedwith brine, dried (MgSO₄), filtered and concentrated. The resultantmaterial was purified by column chromatography on silica gel (20:1:1CH₂Cl₂: MeOH: NH₄OH) to provide the product (558 mg, 48%): ¹H NMR(CDCl₃): δ 1.42 (s, 9H), 1.59 (s, 9H), 1.50-1.62 (m, 4H), 1.71-1.77(2H), 1.82-2.00 (m, 2H), 2.06 (s, 1H), 2.73-2.87 (m, 4H), 3.09-3.13 (m,2H), 3.33 (br s, 1H), 3.75-3.80 (m, 1H), 5.01 (br s, 1H), 7.96 (s, 1H).

Preparation of2-{[[4-tert-butoxycarbonylamino-butyl)-(3-tert-butoxycarbonyl-4,5,6,7-tetrahydro-3H-benzamidazol-4-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester.

To a solution of7-(4-tert-butoxycarbonylamino-butylamino)-4,5,6,7-1-carboxylic acidtert-butyl ester (365 mg, 0.893 mmol) in CH₃CN (12 mL) was added2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (357mg, 1.33 mmol), potassium iodide (14 mg), and diisopropylethylamine(0.311 ml, 1.78 mmol). The reaction mixture was stirred at 40° C. for 17hours. Saturated sodium bicarbonate (15 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×30 mL). The combined organic extracts weredried (MgSO₄), filtered and concentrated. Purification of the crudematerial by column chromatography on silica gel (diethyl ether saturatedwith ammonia) provided the product as a white foam (269mg, 47%): ¹H NMR(CDCl₃): δ 1.41 (s, 9H), 1.34-1.50 (m, 6H), 1.59 (s, 9H), 1.68 (s, 9H),1.60-1.75 (m, 2H), 1.88 (s, 2H), 1.93-2.03 (m, 2H), 2.63-2.76 (m, 4H),2.79-3.01 (m, 2H), 4.04-4.80 (m, 1H), 4.35 (d, 1H, J=16.2 Hz), 4.45 (d,1H, J=16.2 Hz), 4.94-4.99 (m, 1H), 7.26-7.31 (m, 2H), 7.71-7.76 (m, 2H),7.80-7.86 (m, 1H), 7.94 (s, 1H).

Preparation ofN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl)-butane-1,4-diamine(hydrobromide salt). (COMPOUND 110)

To a solution of 2-{[[4-tert-butoxycarbonylamino-butyl)-(3-tert-butoxycarbonyl-4,5,6,7-tetrahydro-3H-benzamidazol-4-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (204 mg, 0.319 mmol) in glacial acetic acid (1.0mL) was added HBr saturated acetic acid (1.5 mL). The reaction mixturewas stirred for 30 minutes, then diethyl ether was added (50 mL). Thewhite precipitate was allowed to settle and the solvent was removed witha pipette. Et₂O (50 mL) was again added then decanted. The resultingprecipitate was dissolved in methanol (1 mL), ether was added (3×50 mL)then it was removed with a pipette. The resultant white powder was driedunder reduced pressure to give 170 mg (78%) of COMPOUND 110: ¹H NMR(D₂O) δ 1.45-1.67 (m, 4H), 1.67-1.86 (m, 2H), 2.06-2.21 (m, 2H),2.50-2.66 (m, 3H), 2.74-2.78 (m, 1H), 2.79-2.89 (m, 2H), 4.26-4.40 (m,3H), 7.55-7.60 (m, 2H), 7.75-7.80 (m, 2H), 8.54 (s, 1H); ¹³C NMR (D₂O) δ20.3, 21.3, 22.0, 25.0, 25.6, 39.7, 47.3, 51.2, 55.4, 114.2, 126.9,127.9, 130.9, 131.7, 132.8, 153.5; ES-MS m/z 339 (M+H). Anal. Calcd. forC₁₇H₂₂N₄.3.5HBr. 2.1H₂O.0.3C₄H₁₀O: C 35.59, H 5.43, N 12.33, Br 41.02.Found: C 35.44, H 5.35, N 12.25, Br 41.26.

Example 111

COMPOUND 111: Preparation ofN¹-(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(HBr salt)

To a stirred solution of2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(154 mg, 0.441 mmol), diisopropylethylamine (0.15 mL, 0.861 mmol) andpotassium iodide (15 mg, 0.090 mmol) in acetonitrile (2.5 mL) was added2-chloromethyl-5,6-dimethyl-1H-benzimidazole (prepared according to theprocedures described in Bridger et al. U.S. patent application Ser. No.09/535,314) (77 mg, 0.426 mmol) and the mixture heated at 60° C. for 18hours. The mixture was then concentrated and the residue diluted withCH₂Cl₂ (30 mL). The solution was washed with saturated aqueous NaHCO₃(1×20 mL) and brine (2×15 mL). The combined aqueous phase was extractedwith CH₂Cl₂ (1×15 mL). The combined organic phase was dried (Na₂SO₄),filtered and concentrated under reduced pressure to give a crude brownfoam. The foam was purified by flash chromatography (1.75 cm ID, 12 gsilica, 50:1:1 CH₂Cl₂: MeOH: NH₄OH) to give pure2-{4-[(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione(60 mg, 28%). ¹H NMR (CDCl₃) δ 1.34-1.51 (m, 2H), 1.53-1.73 (m, 3H),1.81-2.06 (m, 2H), 2.12-2.22 (m, 1H), 2.34 (s, 6H), 2.55-2.89 (m, 4H),3.51 (t, 2H, J=7.3 Hz), 3.93-4.08 (m, 3H), 7.1 (dd, 1H, J=7.5, 4.8 Hz),7.31-7.39 (m, 3H), 7.63-7.67 (m, 2H), 7.72-7.77 (m, 2H), 8.58 (d, 1H,J=4.0 Hz).

To a stirred solution of2-{4-[(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione(60 mg, 0.118 mmol) in ethanol (2.5 mL) was added hydrazine hydrate(0.05 mL, 1.03 mmol) and the mixture stirred at room temperature for 16hours. The mixture was then diluted with diethyl ether, dried (MgSO₄),filtered and concentrated under reduced pressure to give a crude yellowoil. The oil was purified by flash chromatography (1.75 cm ID, 12 gsilica, 10:1:1 CH₂Cl₂: MeOH: NH₄OH) to give pureN¹-(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(18 mg, 38%). ¹H NMR (CDCl₃) δ 1.30-1.46 (m, 4H), 1.60-1.75 (m, 1H),1.82-1.96 (m, 1H), 1.98-2.08 (m, 1H), 2.14-2.24 (m, 1H), 2.35 (s, 6H),2.47-2.59 (m, 3H), 2.65-2.90 (m, 3H), 3.92-4.06 (m, 3H), 7.13 (dd, 1H,J=7.9, 4.8 Hz), 7.34 (s, 2H), 7.40 (d, 1H, J=7.1 Hz), 8.58 (s, 1H, J=3.5Hz).

Following the standard HBr salting procedure D:N¹-(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(17 mg, 0.045 mmol) was converted to the HBr salt (28 mg, 97%). ¹H NMR(D₂O) δ 1.46-1.59 (m, 4H), 1.76-1.89 (m, 1H), 1.94-2.08 (m, 1H),2.13-2.24 (m, 1H), 2.29-2.63 (m, 8H) containing 2.41 (s, 6H), 2.77-2.92(m, 3H), 2.95-3.05 (m, 2H), 4.33 (d, 1H, J=16.2 Hz), 4.43-4.52 (m, 2H),7.56 (s, 2H), 7.81-7.88 (m, 1H), 8.30-8.35 (m, 1H), 8.58-8.63 (m, 1H).¹³C NMR (D₂O) δ 19.96, 20.38, 25.03, 25.38, 27.62, 39.50, 47.99, 51.72,60.53, 113.72, 125.86, 129.54, 137.22, 139.31, 140.54, 147.98, 150.29,151.36. ES-MS m/z 378 (M+H). Anal Calc. for C₂₃H₃₁N₅.3.0HBr.1.5H₂O: C,42.68; H, 5.76; N, 10.82; Br, 37.03. Found: C, 42.53; H, 5.64; N, 10.59;Br, 37.32.

Example 112

COMPOUND 112: Preparation ofN¹-[1-(1H-Benzimidazol-2-yl)-ethyl]-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of 1-(1H-Benzimidazol-2-yl)-ethanone

A solution of 1,2-phenylene diamine (3.25 g, 0.030 mol) and L-lacticacid (2.3 mL, 0.026 mol) in 3 M HCl (15 mL) was refluxed overnight. Thereaction was cooled to room temperature, diluted with EtOAc (50 mL) andsaturated aqueous Na₂CO₃ and solid Na₂CO₃ to pH 10. The aqueous phasewas washed with EtOAc (1×50 mL) and the combined organic extracts dried(Na₂SO₄) and concentrated to afford a brown-orange solid which was usedin the next reaction without further purification.

To a stirred solution of the crude alcohol from above (0.026 mol) in dryCH₂Cl-₂/MeOH (6:1, 35 mL) was added activated manganese dioxide (85%purity, <5 micron, 23.28 g, 0.228 mol) and the suspension stirredovernight, at which point the black slurry was filtered through a cakeof celite and washed with MeOH (3×50 mL). The combined washings wereconcentrated to afford a dark brown solid. Purification of the crudeproduct by column chromatography on silica gel (CH₂Cl₂/MeOH, 98:2 to95:5) afforded the title compound as a red-brown solid (1.65 g, 39%). ¹HNMR (CD₃OD) δ 2.72 (s, 3H), 7.37 (dd, 2H, J=6, 3 Hz), 7.66-7.73 (br m,2H).

Using General Procedure B: To a solution of8-amino-5,6,7,8-tetrahydroquinoline (266 mg, 1.80 mmol) in MeOH (5 mL)was added 1-(1H-benzimidazol-2-yl)-ethanone (285 mg, 1.78 mmol) and theresultant solution was stirred at room temperature for 4.5 h. SolidNaBH₄ (125 mg, 3.30 mmol) was added to the solution and the mixture wasstirred at room temperature for 30 min. The resultant crude brown oilwas purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 98:2then 96:4) to give the desired amine (125 mg, 24%) as a brown foam andmixture of diastereomers (6:1).

Following General Procedure B: To a stirred solution of the amine fromabove (mixture of diastereomers, 125 mg, 0.43 mmol) and4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (97 mg, 0.45 mmol)in dry CH₂Cl₂ (5 mL) was added NaBH(OAc)₃ (127 mg, 0.59 mmol) and themixture stirred at room temperature overnight. The resultant crude brownoil (215 mg) was purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 98:2 then 96:4) to afford the desired amine (175 mg, 83%)as a brown foam.

To a solution of the phthalimide from above (175 mg, 0.355 mmol) in EtOH(3 mL) was added anhydrous hydrazine (0.06 mL, 1.89 mmol) and themixture stirred overnight. The resultant white solid was filteredthrough filter paper, washing thoroughly with CH₂Cl₂ and the filtrateconcentrated in vacuo. The crude product was purified by radialchromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH, 50:1:1 then25:1:1) to give the desired free amine (67 mg, 52% 2 steps) as a paleyellow oil.

Using General Procedure D: Conversion of the material from above (67 mg,0.18 mmol) to the hydrobromide salt gave COMPOUND 112 (95 mg, 78%) as apale green solid. ¹H NMR (D₂O) mixture of diastereomers δ 1.37-1.55 (m,4H), 1.81-1.85 (m, 1H), 1.83 (d, 3H, J=6.9 Hz), 2.05-2.16 (m, 3H),2.69-2.74 (m, 1H), 2.85 (t, 2H, J=7.8 Hz), 2.86-3.00 (m, 3H), 4.52-4.57(m, 1H), 4.79-4.85 (m, 1H, overlap with HOD), 7.61 (dd, 2H, J=6.3, 3.3Hz), 7.79 (dd, 2H, J=6.3, 3.3 Hz), 7.84 (dd, 1H, J=7.5, 6 Hz), 8.31 (d,1H, J=8.1 Hz), 8.60 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) mixture ofdiastereomers δ 16.56, 20.64, 23.25, 25.19, 25.77, 27.47, 39.46, 48.19,53.93, 58.37, 114.33, 125.82, 127.06, 130.91, 139.02, 140.22, 148.02,152.36, 154.55. ES-MS m/z 364 (M+H). Anal. Calcd. forC₂₂H₂₉N₅.3.1HBr.0.9H₂O.0.4C₄H₁₀O: C, 42.94; H, 5.79; N, 10.61; Br,37.52. Found: C, 42.99; H, 5.58; N, 10.64; Br, 37.42.

Example 113

COMPOUND 113: Preparation ofN¹-(4-fluoro-1H-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(HBr salt)

To a stirred solution of2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(146 mg, 0.418 mmol), diisopropylethylamine (0.15 mL, 0.861 mmol) andpotassium iodide (14 mg, 0.084 mmol) in acetonitrile (2.5 mL) was added2-chloromethyl-7-fluoro-1H-benzimidazole (prepared according to theprocedures described in Bridger et al. U.S. Provisional Application60/232,891 filed 15 Sep. 2000 and from Application 60/234,510 filed 22Sep. 2000) (80 mg, 0.433 mmol) and the mixture heated at 60° C. for 18hours. The mixture was then concentrated and the residue diluted withCH₂Cl₂ (30 mL). The solution was washed with brine (3×15 mL). Thecombined aqueous phase was extracted with CH₂Cl₂ (1×15 mL). The combinedorganic phase was dried (Na₂SO₄), filtered and concentrated underreduced pressure to give a crude brown foam. The foam was purified byflash chromatography (1.75 cm ID, 12 g silica, 50:1:1 CH₂Cl₂: MeOH:NH₄OH) to give pure2-{4-[(4-fluoro-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione(86 mg, 41%). ¹H NMR (CDCl₃) δ 1.33-1.76 (m, 5H), 1.85-2.10 (m, 3H),2.14-2.25 (m, 1H), 2.54-2919 (m, 4H), 3.45-3.55 (m, 2H), 3.98-4.24 (m,3H), 7.29-7.45 (m, 2H), 7.63-7.69 (m, 2H), 7.72-7.77 (m, 2H), 8.56-8.63(m, 1H).

To a stirred solution of2-{4-[(4-fluoro-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione(86 mg, 0.173 mmol) in ethanol (2.0 mL) was added hydrazine hydrate(0.05 mL, 1.03 mmol) and the mixture stirred at room temperature for 20hours. The mixture was then diluted with diethyl ether, dried (MgSO₄),filtered and concentrated under reduced pressure to give a crude yellowoil. The oil was purified by flash chromatography (1.75 cm ID, 12 gsilica, 25:1:1 CH₂Cl₂: MeOH: NH₄OH) to give pureN¹-(4-fluoro-1H-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(29 mg, 46%). ¹H NMR (CDCl₃) δ 1.28-1.47 (m, 4H), 1.63-1.77 (m, 1H),1.85-2.09 (m, 2H), 2.15-2.25 (m, 1H), 2.46-2.60 (m, 3H), 2.65-2.76 (m,2H), 2.79-2.91 (m, 1H), 4.01-4.18 (m, 3H), 6.89 (dd, 1H, J=10.3, 8.0Hz), 7.05-7.11 (m, 1H), 7.12-7.18 (m, 1H), 7.35 (d, 1H, J=7.8 Hz), 7.43(d, 1H, J=7.9 Hz), 8.59 (d, 1H, J=4.4 Hz).

Following the standard HBr salting procedure D:N¹-(4-fluoro-1H-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(29 mg, 0.079 mmol) was converted to the HBr salt (40 mg, 79%). ¹H NMR(D₂O) δ 1.50-1.62 (m, 4H), 1.77-1.91 (m, 1H), 1.98-2.12 (m, 1H),2.15-2.25 (m, 1H), 2.33-2.43 (m, 1H), 2.54-2.64 (m, 1H), 2.81-2.93 (m,3H), 2.97-3.04 (m, 2H), 4.38 (d, 1H, J=16.7 Hz), 4.46-4.55 (m, 2H),7.30-7.37 (m, 1H), 7.49-7.60 (m, 2H), 7.84 (dd, 1H, J=7.9, 6.1 Hz), 8.32(d, 1H, J=8.0 Hz), 8.60 (d, 1H, J=5.6 Hz). ¹³C NMR (D₂O) δ 20.37, 20.44,25.01, 25.33, 27.61, 39.49, 48.39, 51.76, 60.64, 110.31, 111.57, 111.78,125.81, 127.28, 127.38, 139.35, 140.44, 147.80, 149.83 (d, 1C,J_(C-F)=227.9 Hz), 151.35, 152.82. ES-MS m/z 368 (M+H). Anal Calc. forC₂₁H₂₆N₅F.3.0HBr.1.9H₂O: C, 39.14; H, 5.13; N, 10.87; F, 2.95; Br,37.20. Found: C, 39.43; H, 4.99; N, 10.53; F, 2.86; Br, 37.02.

Example 114

COMPOUND 114: Preparation ofN¹-(4-Methoxy-1H-benzoindiazol-2-ylmethyl)-N¹-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine)hydrochloridesalt)

Preparation of(S)-2-{[(4-Amino-butyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-4methoxy-benzoimidazole-1-carboxylicacid tert-butyl ester:

To a solution of(S)-2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(3.65 g, 10.46 mmol) in acetonitrile (52 ml) was added2-chloromethyl-4-methoxy-benzoimidazole-1-carboxylic acid tert-butylester (3.10 g, 10.46 mmol), potassium iodide (87 mg, 0.52 mmol), anddiisopropylethylamine (1.82 ml, 10.46 mmol). The mixture was stirred for16 hours at 50° C. under a N₂ atmosphere. The mixture was concentrated,redissolved in methylene chloride (100 ml) and diluted with H₂O (300ml). The aqueous layer was extracted with methylene chloride (2×75 ml)and the combined organic extracts were dried (Na₂SO₄), filtered, andconcentrated in vacuo to afford a dark orange oil. Purification viacolumn chromatography on silica gel (CH₂Cl₂:MeOH:NH₄OH, 94:5:1, v/v/v)followed by a second purification by column chromatography on silica gel(ethyl acetate:NH₄OH, 98:2, v/v) afforded the product as a yellow oil(4.22 g, 66%). ¹HNMR (CDCl₃) δ 1.23 (m, 2H), 1.45 (m, 2H), 1.69 (s, 9H),1.93 (m, 2H), 2.62 (m, 2H), 2.75 (m, 2H), 3.50 (t, 2H), 3.98 (s, 3H),4.10 (m, 2H), 4.60 (m, 2H), 6.68 (dd, 1H, J=7.89, 2.19 Hz), 6.92 (m,1H), 7.13 (m, 2H), 7.36 (dd, 1H, J=8.77, 2.63 Hz), 7.68 (m, 2H), 7.78(m, 2H), 8.31 (m, 1H).

Preparation ofN-(4-Methoxy-1H-benzoindiazol-2-ylmethyl)-N(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

To a solution of2-{[(4-Amino-butyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-4methoxy-benzoimidazole-1-carboxylicacid tert-butyl ester (4.22 g, 6.93 mmol) in ethanol (69 ml) was addedhydrazine hydrate (1.09 ml, 34.65 mmol). The solution was stirred for 16hours at room temperature under a N₂ atmosphere. A white precipitateformed. Diethyl ether (69 ml) was added to the mixture and the mixturestirred for 10 min. The mixture was filtered and concentrated.Purification via column chromatography on silica gel (CH₂Cl₂:MeOH:NH4OH,94:5:1, v/v/v) afforded the product as a yellow oil (2.60 g, 98%). ¹HNMR(CDCl₃) δ 1.35 (m, 4H), 1.93 (m, 6H), 2.68 (m, 5H), 4.06 (m, 5H), 6.63(d, 1H, J=8.33 Hz), 7.15 (m, 3H), 7.43 (d, 1H, J=7.02 Hz), 8.60 (d, 1H,J=4.38 Hz)

Prepartion of COMPOUND 114

To a solution ofN-(4-Methoxy-1H-benzoindiazol-2-ylmethyl)-N(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diaminedissolved in methanol (20 ml) was added HCl-saturated methanol (50 ml)and the mixture was stirred for 1 hour at room temperature under a N₂atmosphere. The solution was added dropwise to diethyl ether (1.5 l) toyield a chunky white precipitate. The white solid was isolated viasuction filtration under a steady stream of nitrogen, washed withdiethyl ether and dried at 40° C. in vacuo overnight (4.32 g, 76%). ¹HNMR (D₂O) δ 1.52 (m, 4H), 1.78 (m, 1H), 2.00 (m, 1H), 2.13 (m, 1H), 2.36(m, 1H), 2.53 (m, 1H), 2.74 (m, 1H), 2.79 (m, 2H), 2.88 (m, 2H), 4.20(s, 2H), 4.42 (t, 1H), 7.75 (d, 1H, J=7.89 Hz), 7.83 (dd, 1H, J=7.89,5.70 Hz), 7.80 (d, 1H, J=8.33 Hz), 8.38 (m, 2H), 8.57 (d, 1H, J=5.70Hz); ¹³C NMR δ (D₂O) 19.53, 20.12, 20.44, 25.11, 25.23, 27.64, 39.57,51.18, 53.04, 59.60, 124.72, 125.79, 127.50, 139.29, 140.53, 147.21,147.87, 151.71, 152.96, 155.00. ES-MS m/z 326 (M+H). Anal. Calcd. ForC₂₀H₂₈N₄3.91HCl 2.47H₂O: C, 46.95; H, 7.26; N, 10.95; Cl, 27.10. Found:C, 46.93; H, 7.32; N, 11.05; Cl, 27.11.

Example 115

COMPOUND 115:N¹-(4-methyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diaminePreparation of2-{-(4-methyl-1H-indol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione

2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione(95 mg, 0.27 mmol), 2-chloromethyl-4-methyl-1H-benzoimidazole (59 mg,0.33 mmol), N,N-diisopropylethylamine (62 μL, 0.35 mmol), and potassiumiodide (4 mg, 0.03 mmol) in acetonitril (5 mL) were heated at 60° C.overnight. The reaction mixture was cooled and the solvent was removedunder reduced pressure to afford a brown oil. Purification by flashcolumn chromatography on silica gel using NH₄OH/CH₃OH/CH₂Cl₂ (1:2:100)afforded the desired product as an orange foam (109 mg, 81%). ¹H NMR(CDCl₃) δ 1.41-1.71 (m, 5H), 1.89-2.04 (m, 2H), 2.15-2.19 (m, 1H),2.58-2.88 (m, 7H), 3.43-3.51 (m, 2H), 4.01-4.15 (m, 3H), 6.97 (d, 1H,J=7.2 Hz), 7.06-7.14 (m, 2H), 7.39 (d, 1H, J=7.5 Hz), 7.64 (br m, 2H),8.59 (d, 1H, J=4.2 Hz).

Preparation ofN¹-(4-methyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

To a solution of the above amine (109 mg, 0.22 mmol) in ethanol (8 mL)was added hydrazine hydrate (54 μL, 1.10 mmol). The reaction mixture wasstirred for 2 days at room temperature. Then the mixture wasconcentrated to dryness. Purification by radial chromatography on silicagel (1 mm plate, using NH₄OH/CH₃OH/CH₂Cl₂; 1:1:100→1:5:100, gradientelution) afforded the desired product as a yellow oil (45 mg, 56%). ¹HNMR (CDCl₃) δ 1.29-1.45 (m, 4H), 1.66-1.71 (m, 1H), 1.91-2.05 (m, 2H),2.17-2.21 (m, 1H), 2.47-2.55 (m, 3H), 2.64 (s, 3H), 2.67-2.74 (m, 2H),2.80-2.90 (m, 1H), 4.02-4.18 (m, 3H), 6.98 (d, 1H, J=7.2 Hz), 7.07-7.16(m, 2H), 7.40-7.51 (m, 2H), 8.58 (d, 1H, J=3.9 Hz).

Preparation ofN¹-(4-methyl-1H-benzolimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of the above amine (45 mg, 0.12 mmol) in acetic acid (3mL) was added hydrobromic acid saturated acetic acid (2 mL) and thereaction mixture was stirred for 30 minutes. Then it was triturated withdiethyl ether three times to afford a white solid. The solid wasdissolved in methanol (1 mL) and was triturated with diethyl ether threetimes to afford COMPOUND 115 as a white solid (62 mg, 76%). ¹H NMR (D₂O)δ 1.54 (m, 4H), 1.76-1.90 (m, 1H), 1.97-2.09 (m, 1H), 2.17-2.22 (m, 1H),2.36-2.40 (m, 1H), 2.55-2.62 (m, 4H), 2.81-2.88 (m, 3H), 3.00-3.02 (m,2H), 4.35-4.79 (m, 3H), 7.51 (ABq, 2H, J=62.7, 7.8 Hz), 7.79 (t, 1H, J=7.5 Hz), 7.86 (dd, 1H, J=7.5, 6.3 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.61 (d,1H, J=5.7 Hz). ¹³C NMR (D₂O) δ 16.44, 20.33, 20.45, 25.06, 25.39, 27.64,39.52, 48.12, 51.75, 60.50, 111.46, 125.29, 125.89, 126.99, 127.30,130.83, 139.26, 140.56, 148.02, 151.29, 151.38. ES-MS m/z 364 [M+H]⁺.Anal. Calcd. for C₂₂H₂₉N₅.3.1HBr.2.3H₂O: C, 40.30; H, 5.64; N, 10.68;Br, 37.77. Found: C, 40.50; H, 5.56; N, 10.67; Br, 37.48.

Example 116

COMPOUND 116:N¹-(4,5-dimethyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quionlin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of{4-[(4,5-dimethyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-carbamicacid tert-butyl ester

2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione(490 mg, 1.40 mmol), 2-chloromethyl-4,5-dimethyl-1H-benzoimidazole (328mg, 1.68 mmol), N,N-diisopropylethylamine (0.32 mL, 1.82 mmol), andpotassium iodide (23 mg, 0.14 mmol) in acetonitrile (5 mL) were stirredat 60° C. overnight. Then the reaction mixture was cooled and thesolvent was removed under reduced pressure. Purification by flash columnchromatography on silica gel using NH₄OH/CH₃OH/CH₂Cl₂ (2:1:97) affordedthe product impurely as a brown oil (440 mg).

To a solution of the above amine (440 mg, 0.87 mmol) in ethanol (10 mL)was added hydrazine hydrate (0.21 mL, 4.33 mmol). The reaction mixturewas stirred at room temperature overnight. Then the solvent was removedunder reduced pressure and the orange solid was dried in vacuo.Purification by radial chromatography on silica gel (2 mm plate, usingNH₄OH.CH₃—OH/CH₂Cl₂; 1:1:100→1:5:100, gradient elution) affordedpartially pure product (183 mg) as a yellow oil.

To a solution of the above amine (183 mg, 0.49 mmol) in THF (10 mL) wasadded di-tert-butyl dicarbonate. The reaction mixture was stirred atroom temperature for 1 hours. The solvent was removed under reducedpressure to afford a yellow oil. Purification by flash columnchromatography on silica gel using NH₄OH/CH₃OH/CH₂Cl₂ (1:2:97) affordedthe desired product as a yellow oil (67 mg, 29%). ¹H NMR (CDCl₃) δ1.35-1.41 (m, 11H), 1.63-1.67 (m, 2H), 1.91-2.02 (m, 2H), 2.09-2.14 (m,1H), 2.35 (s, 3H), 2.53 (s, 3H), 2.59-2.68 (m, 2H), 2.71-2.81 (m, 2H),2.97-2.99 (m, 2H), 4.24 (dd, 1H, J=9.0, 6.0 Hz), 4.54 (q, 2H, J=14.7Hz), 4.97 (br s, 1H), 6.93 (dd, 1H, J=7.7, 4.8 Hz), 7.05 (d, 1H, J=8.4Hz), 7.22 (d, 1H, J=7.5 Hz), 7.18 (d, 1H, J=8.1 Hz), 8.36 (d, 1H, J=3.6Hz).

Preparation ofN¹-(4,5-dimethyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of the above amine (67 mg, 0.14 mmol) in acetic acid (3mL) was added hydrobromic acid saturated acetic acid (2 mL) and thereaction mixture was stirred for 30 minutes. Then it was triturated withdiethyl ether three times to afford a white solid. The solid wasdissolved in methanol (1 mL) and was triturated with diethyl ether threetimes to afford COMPOUND 116 as a white solid (66 mg, 62%). ¹H NMR (D₂O)δ 1.54 (br m, 4H), 1.79-1.86 (m, 1H), 2.03 (q, 1H, J=12.9 Hz), 2.20 (brd, 1H, J=13.2 Hz), 2.36-2.43 (m, 4H), 2.47 (s, 3 H), 2.52-2.60 (m, 1H),2.81-2.88 (m, 3H), 3.00-3.03 (m, 2H), 4.33-4.79 (m, 3H), 7.46 (ABq, 2H,J=24.9, 8.4 Hz), 7.85 (dd, 1H, J=7.8, 6.0 Hz), 8.33 (d, 1H, J=7.8 Hz),8.60 (d, 1H, J=5.1 Hz). ¹³C NMR (D₂O) δ 13.37, 18.87, 20.28, 20.43,25.04, 25.36, 27.62, 39.50, 47.98, 51.75, 60.42, 110.75, 122.89, 125.85,129.03, 131.47, 135.59, 139.22, 140.53, 147.97, 150.84, 151.38. ES-MSm/z 378 [M+H]⁺. Anal. Calcd. for C₂₃H₃₁N₅.3.0HBr.2.1H₂O: C, 41.98; H,5.85; N, 10.64; Br, 36.42. Found: C, 41.95; H, 5.47; N, 10.39; Br,36.17.

Example 117

COMPOUND 117: Preparation ofN¹-(6-Fluoro-1H-benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine

To a solution of2-[4-(5,6,7,8-Tetrahydroquinolin-8-ylamino)-butyl]-isoindole-1,3-dione(0.17 g, 0.5 mmol), 2-Chloromethyl-5-fluoro-1H-benzimidazole (0.44 g,1.7 mmol), and potassium iodide (5 mg, 0.02 mmol) in anhydrousacetonitrile (5.0 mL) was added diisopropylethylamine (0.13 mL, 0.73mmol) and stirred at 60° C. for 16 hours. The mixture was thenconcentrated under reduced pressure and the residue partitioned betweendichloromethane (20 mL) and brine (15 mL). The organic phase wasseparated and the aqueous phase was extracted with dichloromethane (2×15mL). The combined organic phases were then dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to give a crude residue that waspurified by column chromatography with silica gel (2:98 MeOH/CH₂Cl₂).This afforded2-{4-[(6-Fluoro-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-isoindole-1,3-dioneas an orange solid (0.17 g, 71%).

A solution of the above compound (0.15 g, 0.3 mmol) in anhydrous ethanol(3 mL) was treated with hydrazine monohydrate (0.15 mL, 3.0 mmol) andstirred for 16 h. The white mixture was then filtered, concentratedunder reduced pressure, and purified by column chromatography withsilica gel (4:1:95 methanol:ammonium hydroxide:dichloromethane) to giveCOMPOUND 117 as a pale yellow solid (0.070 g, 58%). ¹H NMR (CDCl₃) δ1.41 (br, 4H), 1.68 (m, 1H), 1.89 (q, 1H, J=7.2 Hz), 2.02 (m, 1H), 2.21(m, 1H), 2.53 (br, 3H), 2.71 (m, 2H), 2.82 (m, 1H), 4.03 (m, 3H), 6.93(t, 1H, J=8.4 Hz), 7.13 (t, 1H, J=6.0 Hz), 7.25 (br, 1H), 7.41 (d, 1H,J=7.8 Hz), 7.49 (m, 1H), 8.57 (d, 4.5 Hz). ¹³C NMR (CDCl₃) δ 21.75,23.00, 26.30, 29.51 (2C), 41.12, 49.69, 51.00, 62.10, 101.63 (br, 1C),110.24 (d, 1C, J=25.52 Hz), 115.72(br, 1C), 122.62, 135.11 (2C), 137.91,146.73, 147.02, 156.83, 157.93, 159.20(d, 1C, J=281.69 Hz). ES-MS m/z368 (M+H). Anal. Calcd. for C₂₁H₂₆N₅F.0.5CH₂Cl₂: C, 62.99; H, 6.64; N,17.08. Found: C, 63.39; H, 6.88; N, 16.77.

Example 118

COMPOUND 118: Preparation ofN¹-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazo[4,5-b]pyridine-2-carbox-aldehyde(prepared as described by Whitten, J. P.; Matthews, D. P.; McCarthy J.R. J Org. Chem. 1986, 51, 1891-1894)

To a solution of 4-azabenzimidazole (605 mg, 5.08 mmol) in DMF (10 mL)under nitrogen was added DIPEA (1.3 mL, 7.5 mmol) followed by SEMC1 (1.1mL, 6.2 mmol). The reaction was stirred at 80° C. for 2 hours and, oncecooled to room temperature, was poured into brine (20 mL) and dilutedwith EtOAc (30 mL). The layers were separated and the aqueous solutionwas extracted with EtAOc (15 mL×2). The combined organic solution wasdried (MgSO₄), filtered and concentrated under reduced pressure.Purification through a short silica plug (CH₂Cl₂/MeOH, 9:1) gave theSEM-protected benzimidazole as an orange oil (984 mg, 77%).

A solution of this material (132 mg, 0.527 mmol) in THF (1.5 mL) wascooled to −78° C. under nitrogen and t-BuLi (1.7 M in pentane, 0.33 mL,0.56 mmol) was added slowly. The resulting dark red solution was warmedto 0° C. and stirred for 10 minutes, before the addition of DMF (0.10mL, 1.3 mmol). The reaction was stirred at room temperature for anadditional 17 hours, then was quenched by the addition of saturatedaqueous NH₄Cl (10 mL). The mixture was extracted with EtOAc (15 mL×2),and the organic solution was dried (MgSO₄), filtered and concentratedunder reduced pressure. Purification by flash column chromatography onsilica (hexane/EtOAc, 4:1, then 1:1) gave the aldehyde as a yellow oil(43.2 mg, 0.156 mmol, 30%). ¹H NMR (CDCl₃) δ −0.09 (s, 9H), 0.91 (t, 2H,J=8.3 Hz), 3.6 (t, 2H, J=8.3 Hz), 6.08 (s, 2H), 7.39 (dd, 1H, J=8.4, 4.8Hz), 8.24 (dd, 1H, J=8.4, 1.2 Hz), 8.62 (dd, 1H, J=4.8, 1.2 Hz), 10.11(s, 1H).

Preparation of2-(4-{(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(2-trimethylsilanyl-ethoxy-methyl)-1H-imidazo[4,5b]pyridin-2-ylmethyl]-amino}-butyl)-isoindole-1,3-dione

A solution of the aldehyde (43.2 mg, 0.156 mmol) and2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isolindole-1,3-dione(63 mg, 0.18 mmol) in CH₂Cl₂ (1 mL) was stirred at room temperatureunder nitrogen for 35 minutes, then NaBH(OAc)₃ (53 mg, 0.25 mmol) wasadded. The reaction was stirred for an additional 17.5 hours, then wasdiluted with CH₂Cl₂ (5 mL) and washed with 1M NaOH (2 mL×2) and brine (2mL). The organic solution was dried (MgSO₄), filtered and concentratedunder reduced pressure. Purification by flash column chromatography onsilica (CH₂Cl₂/MeOH/NH₄OH, 33:1:0.2) gave the tertiary amine as a lightyellow foam (74.2 mg, 0.121 mmol, 78%). ¹H NMR (CDCl₃) δ −0.13 (s, 9H),0.81 (dd, 2H, J=9.3, 7.2 Hz), 1.35-1.48 (m, 2H), 1.53-1.72 (m, 3H),1.87-2.03 (m, 2H), 2.05-2.16 (m, 1H), 2.55-2.64 (m, 2H), 2.72-2.82 (m,2H), 3.46-3.56 (m, 4H), 4.03 (dd, 1H, J=9.3, 6.6 Hz), 4.18 (d, 1H,J=13.8 Hz), 4.41 (d, 1H, J=13.5 Hz), 6.03 (d, 1H, J=10.8 Hz), 6.11 (d,1H, J=10.8 Hz), 6.94 (dd, 1H, J=7.7, 4.7 Hz), 7.15 (dd, 1H, J=7.8, 4.8Hz), 7.23 (d, 1H 7.66-7.71 (m, 2H), 7.76-7.80 (m, 2H), 7.92 (dd, 1H,J=8.1, 1.2 Hz), 8.30 (dd, 1H, J=4.7, 1.4 Hz), 8.40 (d, 1H, J=3.3 Hz).

Preparation ofN¹-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

A solution of the phthalimide (74.2 mg, 0.121 mmol) and hydrazinemonohydrate (0.06 mL, 1.2 mmol) in EtOH (1.5 mL) was heated at refluxunder nitrogen for 1 hour. The excess solvent was then removed underreduced pressure. The residue was taken up into saturated aqueous NaHCO₃(5 mL) and extracted with CH₂Cl₂ (10 mL×3). The combined organicsolution was dried (Na₂SO₄), filtered and concentrated under reducedpressure, giving the crude primary amine as a colourless oil (55 mg,95%).

To a solution of this material in CH₂Cl₂ (1.5 mL) was added TFA (0.5 mL)and the reaction was stirred at room temperature under nitrogen for 3hours. The excess solvent was removed under reduced pressure, theresidue was taken up into saturated aqueous NaHCO₃ (10 mL) and themixture was extracted with CH₂Cl₂ (10 mL×3). The combined organicsolution was dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1) gave the free base as an off-white foam (23mg, 0.066 mmol, 58%). ¹H NMR (CDCl₃) δ 1.27-1.50 (m, 4H), 1.61-1.78 (m,1H), 1.84-1.96 (m, 1H), 1.98-2.10 (m, 1H), 2.14-2.26 (m, 1H), 2.44-2.61(m, 3H), 2.65-2.91 (m, 3H), 4.03-4.15 (m, 3H), 5.09 (br. s, 2H),7.11-7.15 (m, 2H), 7.41 (d, 1H, J=7.8 Hz), 7.88 (d, 1H, J=8.1 Hz), 8.32(d, 1H, J=4.8 Hz), 8.65 (d, 1H, J=4.2 Hz).

Preparation of COMPOUND 118:

A solution of the amine (22.5 mg, 0.064 mmol) and saturated HBr in HOAc(0.5 mL) in glacial HOAc (1.0 mL) was stirred at room temperature for 30minutes. Et₂O (5 mL) was added and the suspension was stirred for 5minutes before the excess solvent was removed by pipette. Theprecipitate was washed with Et₂O (˜2 mL×5), then dried under reducedpressure giving COMPOUND 118 as an off-white powder (35.4 mg, 0.053mmol, 83%). ¹H NMR (D₂O) δ 1.45-1.65 (m, 4H), 1.72-1.89 (m, 1H),1.94-2.08 (m, 1H), 2.12-2.23 (m, 1H), 2.27-2.42 (m, 1H), 2.52-2.64 (m,1H), 2.77-2.92 (m, 3H), 2.94-3.04 (m, 2H), 4.32 (d, 1H, J=16.8 Hz), 4.42(d, 1H, J=16.8 Hz), 4.46 (dd, 1H, J=9.9, 6.0 Hz), 7.73-7.84 (m, 2H),8.30 (d, 1H, J=7.8 Hz), 8.55-8.63 (m, 3H). ¹³C NMR (D₂O) δ 20.4, 20.5,25.1, 25.3, 27.6, 39.6, 49.7, 51.5, 60.4, 119.9, 125.7, 129.4, 137.3,139.2, 140.4, 146.9, 147.6, 151.9, 161.3. ES-MS m/z 351 (M+H). Anal.Calcd. for C₂₀H₂₆N₆.3.2HBr.1.5H₂O.0.7C₂H₄O₂: C, 38.52; H, 5.29; N,12.60; Br 38.32. Found: C, 38.54; H, 5.00; N, 12.63; Br 38.25.

Example 119

COMPOUND 119: Preparation ofN¹-(1H-imidazo[4,5-c]pyridin-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of 5-azabenzimidazole (460 mg, 3.86 mmol) in DMF (8 mL)under nitrogen was added DIPEA (1.0 mL, 5.7 mmol), followed by SEMC1(0.82 mL, 4.6 mmol). The reaction was stirred at 80° C. for 2 hours,then was cooled to room temperature, poured into brine (20 mL) anddiluted with EtOAc (30 mL). The layers were separated and the aqueoussolution was extracted with EtAOc (15 mL×2). The organic solution waswashed with brine (5 mL×3), dried (MgSO₄), filtered and concentratedunder reduced pressure. Purification by flash column chromatography onsilica (CH₂Cl₂/MeOH, 9:1) gave the SEM-protected benzimidazole as anapproximately 1:1 mixture of the two regioisomers (811 mg, 84%).

A solution of this material (802 mg, 3.22 mmol) in THF (10 mL) wascooled to −78° C. under nitrogen and t-BuLi (1.7M in pentane, 2.0 mL,3.4 mmol) was slowly added. The solution was warmed to 0° C. and stirredfor 20 minutes, before the addition of DMF (0.60 mL, 7.7 mmol). Thereaction was stirred for an additional 15 hours, while slowly warming toroom temperature. Saturated aqueous NH₄Cl (25 mL) was added and themixture was extracted with EtOAc (25 mL×2). The combined organicsolution was dried (MgSO₄), filtered and concentrated under reducedpressure. Attempted purification by flash column chromatography onsilica (CH₂Cl₂/MeOH, 19:1) gave the aldehyde as a mixture containingstarting material, DMF and some other unidentified species. Thismaterial was used as is in the reductive amination.

This material and2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isolindole-1,3-dione(74 mg, 0.21 mmol) were stirred in CH₂Cl₂ (1.5 mL) for 25 minutes, thenNaBH(OAc)₃ (61 mg, 0.29 mmol) was added. The reaction was stirred for 16hours, then was diluted with CH₂Cl₂ (5 mL) and washed with 1M NaOH (2mL×2) and brine (5 mL). The organic solution was dried (MgSO₄), filteredand concentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 49:1:0.25) gave thetertiary amine as an approximately 55% by weight mixture with theSEM-protected azabenzimidazole (140 mg, 0.126 mmol, 4% from theSEM-protected 5-azabenzimidazole).

A solution of this material and hydrazine monohydrate (0.06 mL, 1.2mmol) in EtOH (1.5 mL) was heated at reflux under nitrogen for 1 hour.The excess solvent was evaporated under reduced pressure and the residuewas taken up into saturated aqueous NaHCO₃ (5 mL) and extracted withCH₂Cl₂ (10 mL×3). The combined organic solution was dried (Na₂SO₄),filtered and concentrated under reduced pressure. Purification by flashcolumn chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 9:1:0.05, then MeOH)gave the primary amine as a light yellow foam (2:1 mixture ofregioisomers, 40.1 mg, 0.083 mmol, 66%).

To a solution of this material in CH₂Cl₂ (1 mL) was added TFA (0.1 mL,1.3 mmol) and the reaction was stirred at room temperature undernitrogen for 3.5 hours. The solution was diluted with saturated aqueousNaHCO₃ (10 mL) and was extracted with CH₂Cl₂ (10 mL×3). The combinedorganic solution was dried (Na₂SO₄), filtered and concentrated underreduced pressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1) gave the free base as a white foam (10.1mg, 0.029 mmol, 35%).

To a solution of the free base in HOAc (0.5 mL) was added a solution ofsaturated HBr in HOAc (0.25 mL) and the reaction was stirred at roomtemperature for 20 minutes. The solution was diluted with Et₂O (4 mL)and the solvent was removed by pipette. The precipitate was washed withEt₂O (˜2 mL×5), then dried under reduced pressure, giving COMPOUND 119as a white powder (14.9 mg, 0.022 mmol, 75%). ¹H NMR (D₂O) δ 1.48-1.67(m, 4H), 1.72-1.88 (m, 1H), 1.96-2.08 (m, 1H), 2.12-2.22 (m, 1H),2.28-2.40 (m, 1H), 2.53-2.65 (m, 1H), 2.79-3.02 (m, 5H), 4.29 (d, 1H,J=16.4 Hz), 4.39 (d, 1H, J=16.6 Hz), 4.44 (dd, 1H, J=11.1, 6.0 Hz), 7.81(dd, 1H, J=8.1, 6.0 Hz), 8.11 (d, 1H, J=6.6 Hz), 8.29 (d, 1H, J=7.8 Hz),8.50 (d, 1H, J=6.9 Hz), 8.59 (d, 1H, J=5.4 Hz), 9.16 (s, 1H). ¹³C NMR(D₂O) δ 20.4, 20.5, 25.0, 25.2, 27.6, 39.6, 49.6, 51.4, 60.2, 111.6,125.6, 132.7, 133.9, 138.3, 139.2, 140.3, 147.5, 152.1, 162.5. ES-MS m/z351 (M+H). Anal. Calcd. for C₂₀H₂₆N₆.3.3HBr.1.2C₂H₄O₂: C, 39.02; H,4.98; N, 12.19; Br 38.24. Found: C, 38.90; H, 5.03; N, 12.50; Br 38.10.

Example 120

COMPOUND 120:N¹-(5-trifluoromethyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of2-{4-[(5,6,7,8-tetrahydro-quinolin-8-yl)-(5-trifluoromethyl-1H-benzoimidazol-2-ylmethyl)-amino]-butyl}-isoindole-1,3-dione

2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione(160 mg, 0.46 mmol) and2-chloromethyl-6-trifluoromethyl-1H-benzoimidazole (129 mg, 0.55 mmol),N,N-diisopropylethylamine (100 μL, 0.60 mmol), and potassium iodide (8mg, 0.05 mmol) in acetonitrile were stirred at 40° C. for 3 days. Thenthe reaction mixture was cooled and the solvent was removed underreduced pressure to afford a red oil. Purification by flash columnchromatography on silica gel using NH₄OH/CH₃OH/CH₂Cl₂ (1:2:97) affordedthe product as an orange foam (190 mg, 76%). ¹H NMR (CDCl₃) δ 1.37-1.45(m, 5H), 1.56-1.70 (m, 2H), 2.18-2.20 (m, 1H), 2.57-2.61 (m, 1H),2.72-2.80 (m, 3H), 3.49-3.54 (m, 2H), 3.98-4.16 (m, 3H), 7.13-7.15 (m,1H), 7.40-7.45 (m, 2H), 7.62-7.74 (m, 5H), 7.86 (br m, 1H), 8.62 (br m,1H).

Preparation of2-{[(4-amino-butyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-5-trifluoromethyl-benzoimidazole-1-carboxylicacid tert-butyl ester

To a solution of the above amine (190 mg, 0.35 mmol) in ethanol (10 mL)was added hydrazine hydrate (80 μL, 1.74 mmol). The reaction mixture wasstirred overnight at room temperature and then the solvent was removedunder reduced pressure. Purification by radial chromatography on silicagel (1 mm plate, using NH₄OH/CH₃OH/CH₂Cl₂; 1:1:100→1:4:100, gradientelution) afforded the product partially clean as a yellow oil (140 mg).

To a solution of the above amine (140 mg, 0.34 mmol) in THF (10 mL) wasadded di-tert-butyl dicarbonate (146 mg, 0.67 mmol). The reactionmixture was stirred for 1 hour and the solvent was removed under reducedpressure to yield a yellow oil. Purification by radial chromatography onsilica gel (I mm plate, using NH₄OH/CH₃OH/CH₂Cl₂; 1:1:100) afforded thedesired product as a yellow oil (34 mg, 19% over two steps). ¹H NMR(CDCl₃) δ 1.45-1.48 (m, 9H), 1.68-1.76 (m, 1H), 1.92 (q, 1H, J=12.3 Hz),2.02-2.07 (m, 1H), 2.18-2.22 (m, 1H), 2.31 (br s, 1H), 2.51-2.60 (m,1H), 2.60-2.72 (m, 2H), 2.75-2.91 (m, 3H), 4.03 (t, 1H, J=6.3 Hz), 4.10(d, 1H, J=11.4 Hz), 4.48 (br t, 1H), 7.17 (dd, 1H, J=7.2, 4.8 Hz), 7.44(d, 2H, J=8.1 Hz), 7.56 and 7.73 (d, total 1H, J=7.2 Hz), 7.79 and 7.94(s, total 1H), 8.59 (s, 1H).

Preparation ofN¹-(5-trifluoromethyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of the above amine (34 mg, 0.07 mmol) in acetic acid (2mL) was added hydrobromic acid saturated acetic acid (2 mL) and thereaction mixture was stirred for 30 minutes. Then it was triturated withdiethyl ether five times to afford COMPOUND 120 as a white solid (29mg,60%). ¹H NMR (D₂O) δ 1.55 (br s, 4H), 1.83-1.86 (m, 1H), 2.05 (q, 1H,J=11.6 Hz), 2.17-2.21 (m, 1H), 2.37 (br s, 1H), 2.57-2.59 (m, 1H), 2.88(br s, 3H), 3.00-3.01 m, 2H), 4.37-4.59 (m, 3H), 7.82-7.93 (m, 3H), 8.17(s, 1H), 8.32 (d, 1H, J=7.5 Hz), 8.62 (d, 1H, J=5.4 Hz). ¹³C NMR (D₂O) δES-MS m/z 418 [M+H]⁺. Anal. Calcd. for C₂₂H₂₆N₅F_(3-.)3.0HBr.2.0H₂O: C,37.95; H, 4.78; N, 10.06; Br, 34.43. Found: C, 37.86; H, 4.61; N, 9.89;Br, 34.71.

Example 121 COMPOUND 121:N¹-(5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt).

Preparation of2-{4-[(5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione

To a solution of 2-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (497mg, 2.67 mmol) in dioxane/water (10 mL:1 mL) was added selenium (IV)oxide (326 mg, 2.94 mmol). The reaction mixture was heated to 110° C.overnight. Then the mixture was cooled and the solvent was removed invacuo to afford a dark brown solid. Purification by flash columnchromatography on silica gel using 2%CH₃OH/CH₂Cl₂ afforded the productas a yellow oil (180 mg), which was used without further purification.

To a solution of the above crude aldehyde (180 mg, 0.97 mmol) and2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione(372 mg, 1.06 mmol) in CH₂Cl₂ (10 mL) was added sodiumtriacetoxyborohydride (410 mg, 1.93 mmol). The reaction mixture wasstirred at room temperature for 3 days. Then the solvent was removedunder reduced pressure to afford a yellow oil. Purification by flashcolumn chromatography on silica gel using 2%CH₃OH/CH₂Cl₂ afforded theproduct as a yellow oil (135 mg, 27%). ¹H NMR (CDCl₃) δ 1.42-1.47 (m,2H), 1.56-1.63 (m, 2H), 1.93-1.96 (m, 2H), 2.06-2.07 (m, 2H), 2.22 (t,2H, J=6.0 Hz), 2.60-2.67 (m, 3H), 2.70 (m, 1H), 2.95 (t, 2H, J=6.0 Hz),3.56 (t, 2H, J=6.0 Hz), 4.01 (t, 1H, J=6.0 Hz), 4.16 (ABq, 2H, J=42.0,15.0 Hz), 4.29-4.35 (m, 1H), 4.51 (br s, 1H), 4.58-4.66 (m, 1H), 6.94(d, 1H, J=7.2 Hz), 7.01-7.06 (m, 1H), 7.09 (t, 1H, J=8.1 Hz), 7.29 (d,1H, J=7.5 Hz), 7.47 (d, 1H, J=8.1 Hz), 7.68-7.70 (m, 2H), 7.78-7.81 (m,2H), 8.41 (d, 1H, J=3.9 Hz).

Preparation of2-{4-[(5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione

To a solution of the above amine (135 mg, 0.26 mmol) in ethanol (10 mL)was added hydrazine hydrate (63 μL, 1.30 mmol). The reaction mixture wasstirred overnight. Then the solvent was removed under reduced pressureto afford a yellow oil. Purification by radial chromatography on silicagel (1 mm plate, using NH₄OH/CH₃OH/CH₂Cl₂; 1:1:100→1:6: 100, gradientelution) afforded the product as a yellow oil (47 mg, 46%). ¹H NMR(CDCl₃) δ 1.30-1.47 (m, 4H), 1.67-1.69 (m, 2H), 1.86-2.00 (m, 4H),2.08-2.10 (m, 1H), 2.21 (t, 2H, J=6.0 Hz), 2.54-2.69 (m, 4H), 2.74-2.79(m, 1H), 2.95 (t, 2H, J=6.0 Hz), 4.08 (ABq, 2H, J=38.1, 9.6 Hz),4.04-4.10 (m, 1H), 4.27-4.31 (m, 1H), 4.54-4.60 (m, 1H), 6.95 (d, 1H,J=7.2 Hz), 7.02 (dd, 1H, J=7.7, 4.5 Hz), 7.10 (t, 1H, J=7.2 Hz), 7.32(d, 1H, J=7.5 Hz), 7.48 (d, 1H, J=8.1 Hz), 8.46 (d, 1H, J=4.5 Hz).

Preparation of N¹-(5,6-dihydro-4H-imidazo[4,51-ij]quinolin-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

To a solution of the above amine (47 mg, 0.12 mmol) in acetic acid (3mL) was added a hydrobromide saturated acetic acid (2 mL). The reactionmixture was stirred for 30 minutes. Then it was triturated with diethylether three times. The pale yellow solid was dried in vacuo,re-dissolved in methanol (1 mL), and triturated with diethyl ether threetimes. The resulting solid was dried in vacuo overnight (54.7 mg, 68%).¹H NMR (D₂O) δ 1.55 (br s, 4H), 1.76-1.90 (m, 1H), 2.15 (q, 1H, J=17.4Hz), 2.30-2.32 (m, 1H), 2.33-2.42 (m, 3H), 2.52-2.59 (m, 1H), 2.80-2.88(m, 3H), 3.01-3.09 (m, 4H), 4.34-4.58 (m, 5H), 7.38 (d, 1H, J=7.2 Hz),7.50-7.61 (m, 2H), 7.85 (dd, 1H, J=7.5, 6.0 Hz), 8.34 (d, 1H, J=7.8 Hz),8.61 (d, 1H, J=6.0 Hz). ¹³C NMR (D₂O) δ 20.43, 22.12, 23.04, 25.05,25.45, 27.68, 39.50, 43.86, 46.85, 51.94, 60.59, 111.29, 123.82, 125.92,126.19, 127.36, 129.06, 139.36, 140.64, 148.09, 149.50, 151.30. ES-MSm/z 390 [M+H]⁺. Anal. Calcd. for C₂₄H₃₁N₅.3.0HBr.2.1H₂O: C, 43.02, H,5.75; N, 10.45; Br, 35.77. Found: C, 42.86; H, 5.75; N, 10.49; Br,35.88.

Example 122

COMPOUND 122:N¹-(1-allyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of(1-allyl-1H-benzoimidazol-2-yl)-methanol

To a solution of (1H-benzoimidazol-2-yl)-methanol (501 mg, 3.38 mmol)and allyl bromide (0.29 mL, 3.38 mmol) in DMF (15 mL) was addedN,N-diisopropylethylamine (0.71 mL, 4.06 mmol). The reaction mixture wasstirred at 60° C. overnight. Then the mixture was cooled to roomtemperature and quenched with saturated NaHCO₃ (25 mL). Then it wasextracted with CH₂Cl₂ (3×25 mL). The combined organic layer was washedwith brine (2×25 mL), dried (MgSO₄), filtered, concentrated, and driedin vacuo to afford a brown oil. Purification by flash columnchromatography on silica gel using 2% CH₃OH/CH₂Cl₂ afforded the productas a yellow oil (180 mg, 28%). ¹H NMR (CDCl₃) δ 4.85 (br s, 5H), 4.98(d, 1H, J=17.1 Hz), 5.17 (d, 1H, J=10.5 Hz), 5.88-6.01 (m, 1H),7.20-7.26 (m, 3H), 7.66 (t, 1H, J=3.9 Hz).

Preparation of 1-allyl-1H-benzoimidazole-2-carbaldehyde

To a solution of the above alcohol (180 mg, 0.96 mmol) in CH₂Cl₂ (10 mL)was added manganese (IV) oxide (831 mg, 9.56 mmol). The reaction mixturewas stirred for 4 hours. Then the mixture was filtered through a layerof celite and the filtrate was concentrated to dryness to afford ayellow oil (158 mg, 88%). ¹H NMR (CDCl₃) δ 5.02 (d, 2H, J=15.0 Hz),5.16-5.27 (m, 2H), 5.96 (br s, 1H), 7.39-7.44 (m, 3H), 7.92 (d, 1H,J=6.0 Hz), 10.09 (s, 1H).

Preparation of2-{4-[(1-allyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione

To a solution of the above aldehyde (158 mg, 0.85 mmol) and2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione(326 mg, 0.93 mmol) in CH₂Cl₂ (10 mL) was added sodiumtriacetoxyborohydride (360 mg, 1.70 mmol). The reaction mixture wasstirred overnight. Then the solvent was removed under reduced pressureto afford a yellow foam. Purification by flash column chromatography onsilica gel using NH₄0H/CH₃OH/CHCl₂ (0:2:98→1:2:98) to afford the productas a yellow oil (165 mg, 37%), which was used without furtherpurification.

The above amine (165 mg, 0.32 mmol) in concentrated H₂SO₄ (2 mL)/water(20 mL) was refluxed overnight. Then the reaction was cooled andbasified to pH=11 with 10 N NaOH. Then it was extracted with CHCl₃ (5×25mL). The organic layer was dried (Na₂SO₄), filtered, concentrated, anddried in vacuo to afford a yellow oil. Purification by radialchromatography on silica gel (1 mm plate, using NH₄OH/CH₃OH/CH₂Cl₂;1:1:100→1:6:100) to afford the product as a yellow oil (23 mg, 19%). ¹HNMR (CDCl₃) δ 1.23-1.46 (m, 4H), 1.65-1.70 (m, 1H), 1.93-2.10 (m, 3H),2.53 (t, 2H, J=6.9 Hz), 2.62 (t, 2H, J=7.8 Hz), 2.68-2.70 (m, 1H),2.75-2.80 (m, 1H), 4.03-4.13 (m, 3H), 4.81 (d, 1H, J=18.0 Hz), 5.02-5.09(m, 2H), 5.47 (dm, 1H, J=16.2 Hz), 5.84-5.96 (m, 1H), 7.02 (dd, 1H,J=7.5, 4.8 Hz), 7.18-7.24 (m, 2H), 7.29-7.33 (m, 3H), 7.67-7.72 (m, 1H),8.46 (d, 1H, J=4.2 Hz).

Preparation ofN¹-(1-allyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrhaydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of the above amine (23 mg, 0.06 mmol) in acetic acid (3mL) was added hydrobromide saturated acetic acid (2 mL). The reactionmixture was stirred for 30 minutes. Then it was triturated with diethylether five times to afford COMPOUND 122 as a cream-coloured solid, whichwas dried in vacuo for three days. ¹H NMR (D₂O) δ 1.54 (s, 4H),1.74-1.88 (m, 1H), 2.05 (q, 1H, J=10.5 Hz), 2.17-2.22 (m, 1H), 2.39-2.43(m, 1H), 2.54-2.59 (m, 1H), 2.78-2.88 (m, 3H), 3.01 (br d, 2H, J=4.8Hz), 4.49 (dd, 1H, J=10.8, 5.7 Hz), 4.50 (ABq, 2H, J=57.5, 17.7 Hz),5.09-5.14 (m, 3H), 5.35 (d, 1H, J=10.2 Hz), 6.01-6.14 (m, 1H) 7.61-7.67(m, 2H), 7.80-7.89 (m, 3H), 8.35 (d, 1H, J=7.8 Hz), 8.63 (d, 1H, J=5.7Hz). ¹³C NMR (D₂O) δ 20.42, 25.03, 25.47, 27.69, 39.50, 47.43, 47.62,52.00, 60.90, 113.16, 114.52, 119.04, 125.95, 126.94, 127.31, 130.34,130.57, 132.81, 139.37, 140.65, 148.13, 151.09, 151.68. ES-MS m/z 390[M+H]⁺. Anal. Calcd. for C₂₄H₃₁N₅.3.0HBr.2.0H₂O: C, 43.13; H, 5.73; N,10.48; Br, 35.87. Found: C, 43.09; H, 5.60; N, 10.28; Br, 36.08.

Example 123

COMPOUND 123: Preparation ofN¹-(1-Allyl-1H-benzimidazol-2-ylmethyl)-N¹-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine(hydrochloride salt) Preparation ofN-(5,6,7,8-Tetrahydro-quinolin-8yl)-butane-1,4-diamine

To a solution of2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(15.0 g, 42.98 mmol) dissolved in ethanol (215 ml) was added hydrazinehydrate (13.4 ml). The solution was stirred for 16 hours at roomtemperature under a N₂ atmosphere. A white precipitate formed. Diethylether (215 ml) was added and the mixture was stirred for 10 min thenfiltered and concentrated. Purification via column chromatography onsilica gel (CH₂Cl₂:MeOH:NH₄OH, 96:3:1, v/v/v) afforded the product as abrown oil (6.77 g, 74%). ¹H NMR (CDCl₃) δ 1.57 (m, 9H), 2.05 (m, 2H),2.75 (m, 6H), 3.78 (t, 1H), 7.06 (dd, 1H, J=7.89, 4.82 Hz), 7.37 (d, 1H,J=7.89 Hz), 8.39 (d, 1H, J=4.82 Hz).

Preparation of[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-carbamic acidtert-butyl ester

To a solution of N-(5,6,7,8-tetrahydro-quinolin-8yl)-butane-1,4-diamine(6.77 g, 30.9 mmol) in tetrahydrofuran (155 ml) was added slowlytriethylamine (4.30 ml, 30.9 mmol) and Boc-ON (7.60 g, 30.9 mmol). Themixture was stirred for 72 hours at room temperature under a N₂atmosphere. The mixture was concentrated and purified by columnchromatography on silica gel (CH₂Cl₂:MeOH:NH₄OH, 96:3:1, v/v/v). Asecond purification by column chromatography on silica gel (ethylacetate) afforded the product as a brown oil (8.03 g, 80%). ¹H NMR(CDCl₃) δ 1.43 (s, 9H), 1.60 (s, 4H), 1.78 (m, 2H), 1.99 (m, 2H), 2.78(m, 5H), 3.15 (m, 2H), 3.77 (t, 1H), 4.87 (s, 1H), 7.07 (dd, 1H, J=7.45,4.82 Hz), 7.83 (d, 1H, J=7.89 Hz), 8.38 (d, 1H, J=4.38 Hz).

Preparation of{4-[1-Allyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-carbamicacid tert-butyl ester

To a solution of[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-carbamic acidtert-butyl ester (5.12 g, 16.04 mmol) in tetrahydrofuran (80 ml) wasadded 1-allyl-1H-benzoimidazole-2-carbaldehyde (3.0 g, 16.04 mmol) andpotassium carbonate (2.22 g, 16.04 mmol). The mixture was stirred for 1hour then filtered, concentrated and diluted with methylene chloride (80ml). Sodium triacetoxyborohydride (6.80 g, 32.08 mmol) was added and themixture was stirred for 16 hours at room temperature under a N₂atmosphere. The reaction mixture was quenched with a solution ofsaturated aqueous NaHCO₃ (100 ml). Extract with methylene chloride(2×100 ml). The combined organic extracts were dried (Na₂SO₄), filtered,and concentrated in vacuo to afford a brown oil. Purification via columnchromatography on silica gel (CH₂Cl₂:MeOH:NH₄OH, 96:3:1, v/v/v) affordedthe product as a white foam (4.64 g, 74%). ¹H NMR (CDCl₃) δ 1.41 (s,1H), 1.63 (s, 3H), 1.99 (m, 3H), 2.36 (m, 3H), 2.99 (m, 2H), 4.01 (s,2H), 4.13 (m, 1H), 4.80 (m, 2H), 5.07 (m, 2H), 5.40 (d, 1H, J=18 Hz),5.91 (m, 1H), 7.02 (dd, 1H, J=7.45, 4.82 Hz), 7.31 (m, 4H), 7.71 (m,1H), 8.47 (d, 1H, J=3.95 Hz).

Preparation of COMPOUND 123

To a solution of{4-[1-Allyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-carbamicacid tert-butyl ester (5.84 g, 15.01 mmol) in methanol (20 ml) was addedHCl-saturated methanol (40 ml) and the mixture stirred for 1.5 hours atroom temperature under a N₂ atmosphere. The solution was added dropwiseto diethyl ether (1.5 l) to yield a chunky white precipitate. The whitesolid was isolated via suction filtration under a steady stream ofnitrogen, washed with diethyl ether and dried at 40° C. in vacuoovernight (4.92 g, 73%). ¹H NMR (D₂O) δ 1.56 (s, 4H), 1.81 (m, 1H), 2.07(m, 2H), 2.41 (m, 2H), 2.89 (m, 2H), 3.54 (m, 2H), 4.49 (m, 3H), 5.10(m, 3H), 5.37 (d, 1H, J=10.52 Hz), 6.08 (m, 1H), 7.63 (m, 1H), 7.88 (m,3H), 8.37 (d, 1H, J=8.33 Hz), 8.67 (d, 1H, J=5.26 Hz); ¹³C NMR (D₂O) δ13.47, 19.30, 23.92, 24.36, 26.58, 38.41, 46.36, 46.52, 50.85, 59.76,65.34, 112.09, 113.34, 118.0,124.88, 125.87, 126.29, 129.19, 131.60,138.27, 139.55, 147.09, 149.90, 150.56. ES-MS m/z 390 (M +H). Anal.Calcd. For (C₂₄H₃₁N₅)2.87(HCl)1.51(H₂O)0.47(C₄H₁₀O): C, 55.91; H, 7.54;N, 12.60; Cl, 18.27. Found: C, 55.91; H, 7.55; N, 12.60; Cl, 18.27.

Example 124

COMPOUND 124:N¹-(1-cyclopropylmethyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of(1-cyclopropylmethyl-1H-benzoimidazol-2-yl)-methanol

To a solution of (bromomethyl)cyclopropane (0.39 mL, 4.02 mmol) and(1H-benzoimidazol-2-yl)-methanol (596 mg, 4.02 mmol) in DMF (10 mL) wasadded N,N-diisopropylethylamine (0.84 mL, 4.82 mmol). The reactionmixture was stirred at 60° C. for 3 days. Then it was cooled to roomtemperature and quenched with saturated NaHCO₃ (15 mL) and the phaseswere separated. The aqueous phase was washed with CH₂Cl₂ (3×20 mL). Thenthe combined organic layers were washed with brine (2×30 mL), dried(MgSO₄), filtered, concentrated, and dried in vacuo to afford a darkbrown oil. Purification by flash column chromatography on silica gelusing 2% CH₃OH/CH₂Cl₂ afforded the product as a yellow solid (210 mg,26%). ¹H NMR (CDCl₃) δ 0.40-0.45 (m, 2H), 0.52-0.61 (m, 2H), 1.22-1.33(m, 1H), 4.13 (d, 2H, J=6.6 Hz), 4.88 (s, 2H), 7.22-7.24 (m, 2H),7.36-7.38 (m, 1H), 7.66-7.69 (m, 1H).

Preparation of 1-cyclopropylmethyl-1H-benzoimidazole-2-carbaldehyde

To a solution of the above alcohol (210 mg, 1.05 mmol) in CH₂Cl₂ (15 mL)was added manganese (IV) oxide (910 mg, 10.50 mmol). The reactionmixture was stirred overnight. Then it was filtered through a layer ofcelite and the filtrate was concentrated to dryness to afford a brownoil (160 mg, 76%), which was used without further purification. ¹H NMR(CDCl₃) δ 0.43-0.48 (m, 2H), 0.50-0.58 (m, 2H), 1.33-1.38 (m, 1H), 4.54(d, 2H, J=9.0 Hz), 7.38-7.53 (m, 3H), 7.95 (d, 1H, J=9.0 Hz), 10.12 (s,1H).

Preparation of2-{4-[(1-cyclopropylmethyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]butyl}-isoindole-1,3-dione

To a solution of the above aldehyde (160 mg, 0.80 mmol) and2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione(307 mg, 0.88 mmol) in CH₂Cl₂ (10 mL) was added sodiumtriacetoxyborohydride (339 mg, 1.60 mmol). The reaction mixture wasstirred overnight. Then the solvent was removed under reduced pressureto afford a yellow oil. Purification by flash colunm chromatography onsilica gel using 2% CH₃OH/CH₂Cl₂ afforded the product as a yellow oil(332 mg, 79%). ¹H NMR (CDCl₃) δ 0.17-0.22 (m, 1H), 0.28-0.33 (m, 1H),1.04-1.06 (m, 1H), 1.38-1.45 (m, 2H), 1.51-1.65 (m, 3h), 1.96-2.06 (m,3H), 2.58-2.64 (m, 3H), 2.77-2.81 (m, 1H), 3.52 (t, 2H, J=7.5 Hz),4.04-4.09 (m, 3H), 4.18-4.25 (m, 1H), 4.48-4.55 (m, 1H), 6.96 (dd, 1H,J=7.5, 4.8 Hz), 7.14-7.20 (m, 2H), 7.25-7.34 (m, 2H), 7.63-7.69 (m, 3H),7.70-7.80 (m, 2H), 8.44 (d, 1H, J=3.3 Hz).

Preparation ofN¹-(1-cyclopropylmethyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8,-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

To a solution of the above amine (332 mg, 0.62 mmol) in ethanol (15 mL)was added hydrazine hydrate (0.15 mL, 3.11 mmol). The reaction mixturewas stirred overnight. Then the solvent was removed under reducedpressure to afford a pale yellow oil. Purification by radialchromatography on silica gel (2 mm plate; using NH₄OH/CH₃OH/CH₂Cl₂;1:3:100→1:7:100; gradient elution) afforded the desired product as ayellow oil (168 mg, 67%). ¹H NMR (CDCl₃) δ 0.21-0.23 (m, 1H), 0.28-0.31(m, 1H), 0.42-0.47 (m, 2H), 1.09-1.12 (m, 1H), 1.32-1.41 (m, 3H),1.65-1.73 (m, 1H), 1.95-2.05 (m, 3H), 2.52-2.61 (m, 3H), 2.70-2.73 (m,1H), 2.75-2.81 (m, 3H), 3.66 (s, 2H), 4.03-4.07 (m, 1H), 4.19-4.21 (m,1H), 4.49-4.52 (m, 1H), 7.03 (dd, 1H, J=7.7, 4.5 Hz), 7.15-7.23 (m, 2H),7.31-7.36 (m, 2H), 7.65-7.71 (m, 1H), 8.47 (d, 1H, J=3.9 Hz).

Preparation ofN¹-(1-cyclopropylmethyl-1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of the above amine (142 mg, 0.35 mmol) in acetic acid (3mL) was added hydrobromide saturated acetic acid (2 mL). The reactionmixture was stirred for 30 minutes. Then it was triturated with diethylether three times and the solid was dried in vacuo. The solid was thenre-dissolved in anhydrous methanol (1 mL) and was triturated withdiethyl ether three times. The pale yellow solid (198 mg, 80%) was driedin vacuo overnight. ¹H NMR (D₂O) δ 0.51 (d, 2H, J=4.8 Hz), 0.65 (d, 2H,J=7.5 Hz), 1.31-1.32 (m, 1H), 1.53 (br s, 4H), 1.77-1.91 (m, 1H),2.02-2.23 (m, 2H), 2.42-2.46 (m, 1H), 2.55-2.60 (m, 1H), 2.86 (s, 3H),3.02 (d, 2H, J=4.5 Hz), 4.39 (d, 2H, J=7.2 Hz), 4.47 (s, 1H), 4.45-4.50(m, 1H), 4.65 (d, 1H, J=17.4 Hz), 7.62-7.65 (m, 2H), 7.83-7.89 (m, 3H),8.35 (d, 1H, J=7.8 Hz), 8.64 (d, 1H, J=5.7 Hz). ¹³C NMR (D₂O) δ 4.11,4.15, 14.55, 20.45, 25.06, 25.55, 27.73, 39.50, 48.03, 49.95, 52.08,60.97, 113.35, 114.33, 125.98, 126.80, 127.22, 130.45, 132.94, 139.40,140.67, 148.18, 151.08, 151.32. ES-MS m/z404 [M+H]⁺. Anal. Calcd. forC₂₅H₃₃N₅.3.1HBr.1.5H₂O.0.3C₄H₁₀O: C,44.72; H, 6.03; N, 9.95; Br, 35.20.Found: C, 44.82; H,6.07; N, 9.98; Br, 35.00.

Example 125

COMPOUND 125:N¹-(1-pyridin-2-ylmethyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of1-pyridine-2-ylmethyl-1H-imidazole-2-carbaldehyde

To a solution of the 2-imidazolecarboxaldehyde (545 mg, 5.67 mmol) and2-(bromomethyl)pyridine hydrobromide (1.58 g, 6.24 mmol) in DMF (20 mL)was added N,N-diisopropylethylamine (3.0 mL, 17.01 mmol). The reactionmixture was heated to 80° C. overnight. Then it was cooled and quenchedwith saturated NaHCO₃ (20 mL). It was extracted with CH₂Cl₂ (c×20 mL).The combined organic layers were washed with brine (20 mL), dried(MgSO₄), filtered, concentrated, and dried in vacuo to afford a darkbrown oil. Purification by flash column chromatography on silica gelusing 1% →2% CH₃OH/CH₂Cl₂ afforded the product as a yellow solid (397mg, 37%). ¹H NMR (CDCl₃) δ 5.71 (s, 2H), 7.18-7.24 (m, 2H), 7.32 (s,1H), 7.36 (s, 1H), 7.65 (td, 1H, J=10.4, 1.5 Hz), 8.56 (d, 1H, J=4.5Hz), 9.82 (s, 1H).

Preparation of2-{4-[(1-pyridin-2-ylmethyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione

To a solution of the above aldehyde (543 mg, 2.90 mmol) and2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione(1.11 g, 3.19 mmol) in CH₂Cl₂ (20 mL) was added sodiumtriacetoxyborohydride (1.23 g, 5.80 mmol). The reaction mixture wasstirred overnight. Then it was extracted with saturated NaHCO₃ (3×25mL). The combined aqueous washings were washed once with CH₂Cl₂ (30 mL).The organic layer was dried (MgSO₄), filtered, concentrated, and driedin vacuo to afford a yellow foam. Purification by radial chromatographyon silica gel using NH₄OH/CH₃OH/CH₂Cl₂ (1:1:100) afforded the desiredproduct as a yellow oil (135 mg, 9%). ¹H NMR (CDCl₃) d 1.18-1.28 (m,2H), 1.49-1.67 (m, 3H), 1.75-1.95 (m, 2H), 2.01-2.06 (m, 1H), 2.51-2.777(m, 4H), 3.51 (t, 2H, J=7.2 Hz), 3.87 (s, 2H), 4.00 (dd, 1H, J=6.3, 2.7Hz), 5.70 (ABq, 2H, J=94.8, 16.5 Hz), 6.79 (d, 1H, J=7.6Hz), 6.86 (d,2H, J=7.5, 4.5Hz), 7.12 (dd, 1H, J=7.2, 5.1 Hz), 7.24 (d, 1H, J=7.8Hz),7.55 (td, 1H, J=6.9, 1.8 Hz), 7.66-7.69 (m, 2H), 7.78-7.81 (m, 2H), 8.24(d, 1H, J=3.6 Hz), 8.53 (d, 1H, J=4.8 Hz).

Preparation ofN¹-(1-pyridin-2-ylmethyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

To a solution of the above amine (135 mg, 0.26 mmol) in ethanol (5 mL)was added hydrazine hydrate (60 μL, 1.30 mmol). The reaction mixture wasstirred overnight. Then the solvent was removed under reduced pressureto afford a white solid. Purification by radial chromatography on silicagel (1 mm plate; using NH₄OH/CH₃OH/CH₂Cl₂; 1:3:100→1:8:100) afforded thedesired product as a yellow oil (42 mg, 41%). ¹H NMR (CDCl₃) δ 1.30-1.33(m, 4H), 1.57-1.66 (m, 1H), 1.82-1.97 (m, 2H), 2.02-2.06 (m, 2H),2.51-2.60 (m, 5H), 2.64-2.73 (m, 2H), 3.87 (d, 2H, J=3.0 Hz), 4.02 (dd,1H, J=9.0, 6.0 Hz), 5.69 (ABq, 2H, J=108.0, 18.0 Hz), 6.77 (d, 1H, J=7.8Hz), 6.89 (s, 1H), 6.91-6.94 (m, 1H), 6.96 (d, 1H, J=0.9 Hz), 7.16 (dd,1H, J=7.2, 5.1 Hz), 7.29 (s, 1H), 7.56 (td, 1H, J=7.7, 1.5 Hz), 8.29 (d,1H, J=4.2 Hz), 8.55 (d, 1H, J=4.5 Hz).

Preparation ofN¹-(1-pyridine-2-ylmethyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of the above amine (42 mg, 0.11 mmol) in acetic acid (3mL) was added hydrobromic acid saturated acetic acid (2 mL). Thereaction mixture was stirred for 30 minutes and then it was trituratedwith diethyl ether three times. The resulting precipitate was dried invacuo. The precipitate was dissolved in methanol (1 mL) and trituratedwith diethyl ether three times. The isolated cream solid (66 mg, 83%)was dried in vacuo. ¹H NMR (D₂O) δ 1.44 (br s, 4H), 1.69-1.72 (m, 1H),1.87 (q, 1H, J=12.0 Hz), 2.09 (br d, 2H, J=8.7 Hz), 2.40 (br s, 1H),2.60 (br d, 1H, J=8.1 Hz), 2.84 (br s, 2H), 2.95 (br d, 2H, J=4.8 Hz),4.23 (q, 2H, J=18.9 Hz), 4.32 (m, 1H), 5.71 (d, 2H, J=8.7 Hz), 7.55 (s,2H), 7.64-7.71 (m, 2H), 7.83 (t, 1H, J=6.6 Hz), 8.16 -8.21 (m, 1H), 8.31(d, 1H, J=7.8 Hz), 8.55 (d, 1H, J=5.4 Hz), 8.61 (m, 1H). ¹³C NMR (D₂O) δ20.02, 20.42, 25.00, 25.30, 27.63, 46.66, 50.83, 51.63, 60.15, 119.89,124.23, 124.84, 125.92, 126.11, 139.36, 140.58, 142.86, 146.09, 147.42,148.11, 151.05. ES-MS m/z 391 {M+H]⁺. Anal. Calcd. forC₂₃H₃₀N₆.3.9HBre.1.7H₂O: C, 37.35; H, 4.95; N, 11.28; Br, 42.59. Found:C, 37.50; H, 5.10; N, 11.41; Br, 42.30.

Example 126

COMPOUND 126:N¹-(4-methyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of2-{[[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-4-methyl-imidazole-1-sulfonicacid dimethylamide

To a solution of 4-methylimidazole (1.0 g, 12.18 mmol) and triethylamine(1.3 mL, 12.18 mmol) in CH₂Cl₂ (25 mL) at 0° C. was added dimethylsulfamoyl chloride (3.4 mL, 24.36 mmol). The reaction mixture was warmedto room temperature and was stirred overnight. Then the mixture wasextracted with water (25 mL) and saturated NaCl (2×25 mL). The organiclayer was dried (MgSO₄), filtered, concentrated, and dried in vacuo toafford a pale yellow solid. Purification by flash column chromatographyon silica gel using 5% CH₃OH/CH₂Cl₂ afforded a mixture of product andstarting material as a pale yellow solid, which was used without furtherpurification.

To a solution of the above amine (505 mg, 2.67 mmol) in dry THF (27 mL)at −78° C. and under Ar₂(g) was added n-butyl lithium (1.18 mL, 2.94mmol, 2.5 M in hexanes). After 45 minutes, N,N-dimethylformamide (0.25mL, 3.20 mmol) was added dropwise and the reaction mixture was warmed toroom temperature. After 1.5 hours, the reaction was quenched withsaturated NH₄Cl (6 mL). The solvent was removed under reduced pressure.Then it was dissolved in CH₂Cl₂ (25 mL) and water (10 mL) and the phaseswere separated. The aqueous layer was washed with CH₂Cl₂ (2×25 mL). Thecombined organic washings was washed with brine (50 mL), dried (Na₂SO₄),filtered, concentrated, and dried in vacuo to afford a yellow oil.Purification by flash column chromatography on silica gel using 2%CH₃OH/CH₂Cl₂ afforded an impure yellow oil, which was used withoutfurther purification.

To a solution of the above aldehyde (190 mg, 0.88 mmol) and2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione(338 mg, 0.97 mmol) in CH₂Cl₂ (10 mL) was added sodiumtriacetoxyborohydride (373 mg, 1.76 mmol). The reaction mixture wasstirred for 3 days. Then it was extracted with saturated NaHCO₃ (3×25mL). The organic layer was dried (MgSO₄), filtered, concentrated, anddried in vacuo to afford a yellow foam. Purification by flash columnchromatography on silica gel using 2% CH₃OH/CH₂Cl₂ afforded the productas a pale yellow solid (307 mg, 67%). ¹H NMR (CDCl₃) δ 1.19-1.27 (m,2H), 1.43-1.51 (m, 2H), 1.64-1.78 (m, 2H), 1.91-1.96 (m, 1H), 2.07 (s1H), 2.10-2.14 (m, 1H), 2.53-2.75 (m, 4H), 2.92 (s, 6H), 3.53 (t, 2H,J=7.2 Hz), 4.17 (t, 1H, J=8.4 Hz), 4.25 (q, 2H, J=14.4 Hz), 6.81 (s,1H), 6.94 (dd, 1H, J=7.5, 4.8 Hz), 7.26 (d, 1H, J=6.9 Hz), 7.65-7.70 (m,2H), 7.75-7.81 (m, 2H), 8.31 (d, 1H, J=3.6 Hz).

Preparation ofN¹-(4-methyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

The above amine (300 mg, 0.58 mmol) in 2N HCl (6 mL) was stirred atreflux overnight. The reaction mixture was cooled and basified with 15%aqueous NaOH. Then it was extracted with CH₂Cl₂ (3×15 mL). The combinedorganic washings was washed with saturated NaCl (25 mL), dried (Na₂SO₄),filtered, concentrated, and dried in vacuo to afford a yellow oil.Purification by radial chromatography on silica gel (1 mm plate; usingNH₄OH/CH₃OH/CH₂Cl⁻²; 1:3:100→1:10:100; gradient elution) afforded theproduct as a yellow oil (72.5 mg, 40%). ¹H NMR (CDCl₃) δ 1.24-1.38 (m,4H), 1.63-1.68 (m, 1H), 1.82-1.86 (m, 1H), 1.96-2.00 (m, 1H), 2.10-2.15(m, 1H), 2.21 (s, 3H), 2.42-2.81 (m, 6H), 3.77 (q, 2H, J=15.9 Hz), 3.96(dd, 1H, J=9.2, 6.0 Hz), 6.63 (s, 1H), 7.08 (dd, 1H, J=7.5, 4.8 Hz),7.37 (d, 1H, J=7.5 Hz), 8.45 (d, 1H, J=4.2 Hz).

Preparation ofN¹-(4-methyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of the above amine (72.5 mg, 0.23 mmol) in acetic acid (3mL) was added hydrobromic acid saturated acetic acid (2 mL). Thereaction mixture was stirred for 30 minutes. Then it was triturated withdiethyl ether three times and the precipitate was dried in vacuo. Thesolid was re-dissolved in methanol (1 mL) and triturated an additionalthree times with diethyl ether. The resulting yellow solid (82 mg, 58%)was dried in vacuo. ¹H NMR (D₂O) δ 1.45-1.61 (m, 4H), 1.78-2.01 (m, 2H),2.15-2.19 (m, 1H), 2.25-2.31 (m, 4H), 2.48-2.53 (m, 1H), 2.71-2.78 (m,1H), 2.89-2.91 (m, 2H), 2.98-3.00 (m, 2H), 4.16 (q, 2H, J=18.0 Hz), 4.39(dd, 1H, J=10.7, 5.4 Hz), 7.11 (s, 1H), 7.85 (dd, 1H, J=10.7, 6.3 Hz),8.34 (d, 1H, J=7.8 Hz), 8.59 (d, 1H, J=5.7 Hz). ¹³C NMR (D₂O) δ 9.43,20.24, 20.45, 25.07, 25.32, 27.61, 39.59, 47.07, 51.25, 60.06, 66.48,115.91, 125.84, 125.84, 130.37, 139.25, 140.47, 144.17, 147.98, 151.58.ES-MS m/z 314 [M+H]⁺. Anal. Calcd. for C₁₈H₂₇N₅.3.0HBr.1.8H₂O.0.2C₄H₁₀O:C, 37.42; H, 5.95; N, 11.61; Br, 39.72. Found: C, 37.17; H, 5.65; N,11.37; Br, 40.10.

Example 127

COMPOUND 127: Preparation ofN¹-(1-isopropyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of 1-isopropyl-1H-imidazole (prepared asdescribed by Gridnev, A. A.; Mihaltseva, I. M. Synth. Commun. 1994, 241547-1555)

A solution of isopropylamine (4.25 mL, 50 mmol) in H₂O (5 mL) wasacidified to approximately pH 2 with concentrated H₃PO₄. Glyoxal (40% inH₂O, 7.5 mL, 52 mmol) and formaldehyde (37% in H₂O, 4.0 mL, 49 mmol)were added and the reaction flask was fitted with a reflux condenser anda dropping funnel. The solution was warmed to 90-95° C. and a saturatedaqueous solution of NH₄Cl (10 mL) was added dropwise over 20 minutes.The reaction was stirred at 100° C. for 30 minutes then, once cooled,was made basic (pH˜10) by the addition of solid NaOH. The solution wasextracted with EtOAc (25 mL×3) and the combined organic solution wasdried (Na₂SO₄), filtered and concentrated under reduced pressure.Purification by vacuum distillation (b.p. 57-70° C./0.25 mmHg) gave theimidazole as a colourless liquid (899 mg, 8.16 mmol, 17%). ¹H NMR(CDCl₃) δ 1.47 (d, 6H, J=6.9 Hz), 4.33 (septet, 1H, J=6.8 Hz), 6.95 (s,1H), 7.04 (s, 1H), 7.52 (s, 1H).

Preparation of 1-isopropyl-1H-imidazole-2-carboxaldehyde

A solution of the imidazole (890 mg, 8.08 mmol) in THF (10 mL) undernitrogen was cooled to −78° C. and n-BuLi (2.5M in hexanes, 4.5 mL, 11.3mmol) was added. The bright yellow solution was stirred at 0° C. for 25minutes, then DMF (1.5 mL, 19 mmol) was added. The reaction was stirredat room temperature for one hour, then was quenched by the addition ofsaturated aqueous NH₄Cl (10 mL). The layers were separated and theaqueous solution was extracted with EtAOc (10 mL×2). The combinedorganic solution was dried (Na₂SO₄), filtered and concentrated underreduced pressure. Purification by flash column chromatography on silica(hexane/EtOAc, 1:1) gave the aldehyde as a pale yellow solid (731 mg,5.29 mmol, 65%). ¹H NMR (CDCl₃) δ 1.46 (d, 6H, J=6.6 Hz), 5.46 (septet,1H, J=6.8 Hz), 7.29 (s, 1H), 7.31 (s, 1H), 9.81 (s, 1H).

Preparation of2-{4-[(1-isopropyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione

A solution of the aldehyde (222 mg, 1.61 mmol),2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(354 mg, 1.01 mmol) and NaBH(OAc)₃ (319 mg, 1.51 mmol) in CH₂Cl₂ (7 mL)was stirred at room temperature under nitrogen for 15 hours. Thereaction was diluted with CH₂Cl₂ (10 mL) and washed with 1M NaOH (10 mL)and brine (10 mL). The organic solution was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/MeOH, 19:1) gave the tertiary amine asa white foam (210 mg, 0.45 mmol, 44%). ¹H NMR (CDCl₃) δ 1.27 (d, 3H,J=6.9 Hz), 1.41 (d, 3H, J=6.6 Hz), 1.49-1.72 (m, 3H), 1.78-2.10 (m, 5H),2.46-2.84 (m, 4H), 3.58 (t, 2H, J=7.1 Hz), 3.85 (d, 1H, J=13.5 Hz),3.92-4.02 (m, 2H), 5.07 (septet, 1H, J=6.6 Hz), 6.83 (s, 1H), 6.87 (s,1H), 7.01 (dd, 1H, J=7.5, 4.8 Hz), 7.31 (d, 1H, J=7.5 Hz), 7.69-7.73 (m,2H), 7.79-7.83 (m, 2H), 8.41 (d, 1H, J=3.6 Hz).

Preparation ofN¹-(1-isopropyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

A solution of the phthalimide (206 mg, 0.44 mmol) and hydrazinemonohydrate (0.20 mL, 4.1 mmol) in EtOH (4.5 mL) was heated at refluxfor 1.5 hours. The solvent was removed under reduced pressure, and theresidue was taken up into saturated aqueous NaHCO₃ (10 mL) and extractedwith CH₂Cl₂ (10 mL×3). The organic solution was dried (Na₂SO₄), filteredand concentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1) gave the primaryamine as a pale yellow oil (128 mg, 0.37 mmol, 85%). ¹H NMR (CDCl₃) δ1.26 (d, 3H, J=6.6 Hz), 1.31-1.37 (m, 4H), 1.41 (d, 3H, J=6.6 Hz),1.54-1.77 (m, 3H), 1.86-2.10 (m, 3H), 2.51-2.60 (m, 4H), 2.62-2.86 (m,2H), 3.84 (s, 2H), 4.04 (dd, 1H, J=8.1, 5.7 Hz), 5.07 (septet, 1H, J=6.6Hz), 6.91 (s, 1H), 6.92 (s, 1H), 7.05 (dd, 1H, J=7.7, 4.7 Hz), 7.35 (d,1H, J=7.5 Hz), 8.46 (d, 1H, J=3.3 Hz).

Preparation of COMPOUND 127

To a solution of the free base (121 mg, 0.35 mmol) in glacial HOAc (1.0mL) was added saturated HBr in HOAc (0.5 mL). The reaction was stirredat room temperature for 20 minutes, then was diluted with Et₂O (5 mL).The salt formed an oil and the solvent was removed by pipette. Theresidue was dissolved into anhydrous MeOH (0.5 mL), stirred forapproximately five minutes, then was diluted with Et₂O (5 mL). Thesolvent was again removed by pipette, the insoluble material was washedwith Et₂O (2 mL×2) and dried under reduced pressure, giving thehydrobromide salt as a fine, white powder (136 mg, 0.25 mmol, 71%). ¹HNMR (D₂O) δ 1.45 (d, 6H, J=6.6 Hz), 1.46-1.62 (m, 4H), 1.67-1.84 (m,1H), 1.92-2.16 (m, 2H), 2.20-2.32 (m, 1H), 2.49-2.62 (m, 1H), 2.75-2.94(m, 5H), 4.08 (d, 1H, J=16.5 Hz), 4.23-4.33 (m, 2H), 4.65 (septet, 1H,J=6.6 Hz), 7.37 (d, 1H, J=1.8 Hz), 7.49 (d, 1H, J=1.5 Hz, 7.54 (dd, 1H,J=7.7, 5.6 Hz), 7.95 (d, 1H, J=8.1 Hz), 8.48 (d, 1H, J=4.8 Hz). ¹³C NMR(D₂O) δ 23.0, 24.0, 24.7, 27.4, 30.6, 42.0, 49.0, 52.8, 53.9, 63.4,121.7, 122.6, 127.1, 140.8, 145.4, 145.9, 147.0, 155.7. ES-MS m/z 342(M+H). Anal. Calcd. for C₂₀H₃₁N₅.2.0HBr.1.2CH₄O: C, 47.00; H, 7.03; N,12.93; Br 29.50. Found: C, 47.20; H, 6.92; N, 12.91; Br 29.13.

Example 128

COMPOUND 128: Preparation ofN¹-[1-(2-methoxy-ethyl)-1H-imidazol-2-ylmethyl]-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of imidazol-1-yl-acetic acid ethyl ester

To a 0° C. suspension of NaH (60% in mineral oil, 658 mg, 16.5 mmol) inTHF (20 mL) under nitrogen was slowly added a solution of imidazole(1.03 g, 15.1 mmol) in THF (20 mL). The resulting suspension was stirredat 0° C. for 15 minutes, then ethyl bromoacetate (2.2 mL, 20 mmol) wasadded. The reaction was stirred at room temperature for 4.5 hours, thenwas diluted with H₂O (25 mL). The THF was evaporated under reducedpressure and the remaining aqueous solution was extracted with CH₂Cl₂(25 mL×3). The combined organic solution was dried (Na₂SO₄), filteredand concentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/MeOH, 19:1) gave the ester as a yellowliquid (1.52 g, 9.87 mmol, 65%). ¹H NMR (CDCl₃) δ 1.28 (t, 3H, J=7.1Hz), 4.24 (q, 2H, J=7.1 Hz), 4.68 (s, 2H), 6.95 (s, 1H), 7.09 (s, 1H),7.50 (s, 1H).

Preparation of 1-(2-methoxy-ethyl)-1H-imidazole

A solution of the ester (1.51 g, 9.81 mmol) in THF (25 mL) undernitrogen was cooled to 0° C. and LiAlH₄ (1.0M in THF, 5.0 mL, 5.0 mmol)was slowly added. The reaction was stirred at room temperature for 20minutes, then was quenched by the addition of H₂O (0.2 mL), 15% aqueousNaOH (0.2 mL) and H₂O (0.6 mL). The mixture was filtered with suctionthrough Celite, washing with EtOAc. The filtrate was dried (Na₂SO₄),filtered and concentrated under reduced pressure, giving the crudealcohol as a yellow oil (896 mg, 81%).

To a 0° C. suspension of NaH (60% in mineral oil, 410 mg, 10.3 mmol) inTHF (10 mL) under nitrogen was slowly added a solution of the alcohol(890 mg, 7.94 mmol) in THF (10 mL). The mixture was stirred at 0° C. for10 minutes, then dimethyl sulfate (0.95 mL, 10.0 mmol) was added. Thereaction was stirred at room temperature for an additional 30 minutes,and then THF was removed under reduced pressure. The residue was takenup into H₂O (25 mL) and was extracted with CH₂Cl₂ (25 mL×3). Thecombined organic solution was dried (Na₂SO₄), filtered and concentratedunder reduced pressure. Purification by flash column chromatography onsilica (CH₂Cl₂/MeOH, 19:1) gave the methyl ether as a colourless oil(347 mg, 2.75 mmol, 35%). ¹H NMR (CDCl₃) δ 3.34 (s, 3H), 3.63 (t, 2H,J=5.1 Hz), 4.09 (t, 2H, J=5.1 Hz), 6.97 (s, 1H), 7.05 (s, 1H), 7.52 (s,1H).

Preparation of 1-(2-methoxy-ethyl)-1H-imidazole-2-carboxaldehyde

A solution of the imidazole (342 mg, 2.71 mmol) in THF (3.5 mL) wascooled to −78° C. under nitrogen and n-BuLi (2.5M in hexanes, 1.4 mL,3.5 mmol) was added. The resulting bright yellow solution was stirred at0° C. for 10 minutes, then DMF (0.5 mL, 6.5 mmol) was added. Thereaction was stirred at room temperature for 45 minutes, then wasquenched by the addition of saturated aqueous NH₄Cl (5 mL). The layerswere separated and the aqueous solution was extracted with CH₂Cl₂ (10mL×2). The organic solution was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/MeOH, 32:1) gave the aldehyde as ayellow liquid (1:1 with DMF, 254 mg, 1.12 mmol, 41%). ¹H NMR (CDCl₃) δ3.30 (s, 3H), 3.66 (t, 2H, J=5.1 Hz), 4.58 (t, 2H, J=5.0 Hz), 7.26 (s,1H), 7.27 (s, 1H), 9.80 (s, 1H).

Preparation of2-{4-[[1-(2-methoxy-ethyl)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione

A solution of the aldehyde (170 mg, 1.10 mmol),2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(422 mg, 1.21 mmol) and NaBH(OAc)₃ (324 mg, 1.53 mmol) in CH₂Cl₂ (8 mL)was stirred at room temperature under nitrogen for 16 hours. Thereaction was diluted with CH₂Cl₂ (10 mL) and was washed with 1M NaOH (10mL) and brine (10 mL). The organic solution was dried (Na₂SO₄), filteredand concentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 49:1:0.25) gave thetertiary amine as a white foam (244 mg, 0.50 mmol, 45%). ¹H NMR (CDCl₃)δ 1.20-1.35 (m, 2H), 1.47-1.70 (m, 3H), 1.80-2.16 (m, 3H), 2.55 (t, 2H,J=7.2 Hz), 2.60-2.85 (m, 2H), 3.27 (s, 3H), 3.48-3.67 (m, 4H), 3.87 (s,2H), 3.98 (dd, 1H, J=9.3, 6.0 Hz), 4.24-4.35 (m, 1H), 4.54-4.66 (m, 1H),6.80 (d, 1H, J=1.2 Hz), 6.89 (d, 1H, J=1.2 Hz), 7.00 (dd, 1H, J=7.7, 4.7Hz), 7.31 (d, 1H, J=7.5 Hz), 7.67-7.73 (m, 2H), 7.79-7.84 (m, 2H), 8.40(d, 1H, J=3.9 Hz).

Preparation ofN¹-[1-(2-methoxy-ethyl)-1H-imidazol-2-ylmethyl]-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

A solution of the phthalimide (238 mg, 0.49 mmol) and hydrazinemonohydrate (0.25 mL) in EtOH (5 mL) was stirred at reflux for 1.5hours. The solvent was removed under reduced pressure, the residue wastaken up into saturated aqueous NaHCO₃ (10 mL) and was extracted withCH₂Cl₂ (15 mL×3). The combined organic solution was dried (Na2SO₄),filtered and concentrated under reduced pressure. Purification by flashcolumn chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1) gave theprimary amine as a colourless oil (130 mg, 0.36 mmol, 74%). ¹H NMR(CDCl₃) δ 1.23-1.42 (m, 4H), 1.60-1.75 (m, 1H), 1.84-2.14 (m, 3H),2.48-2.60 (m, 4H), 2.63-2.86 (m, 2H), 3.28 (s, 3H), 3.49-3.56 (m, 1H),3.58-3.66 (m, 1H), 3.83 (s, 2H), 4.03 (dd, 1H, J=8.4, 6.0 Hz), 4.22-4.31(m, 1H), 4.56-4.64 (m, 1H), 6.88 (d, 12H, J=1.5 Hz), 6.93 (d, 1H, J=1.5Hz), 7.04 (dd, 1H, J=7.5, 4.5 Hz), 7.34 (dd, 1H, J=7.5, 1.5 Hz), 8.45(dd, 1H, J=4.5, 1.5 Hz).

Preparation of COMPOUND 128

To a solution of the free base (48 mg, 0.13 mmol) in glacial AcOH (1.0mL) was added saturated HBr in AcOH (0.5 mL). The reaction was stirredat room temperature for 20 minutes, then was diluted with Et₂O (5 mL).The salt formed a yellow oil and the solvent was removed by pipette. Theresidue was dissolved into anhydrous MeOH (0.5 mL), stirred forapproximately five minutes, then was diluted with Et₂O (5 mL). Thesolvent was again removed by pipette, the insoluble material was washedwith Et₂O (2 mL×2) and dried under reduced pressure, giving thehydrobromide salt as a fine, off-white powder (76 mg, 0.12 mmol, 87%).¹H NMR (D₂O) δ 1.41-1.60 (m, 4H), 1.74-1.88 (m, 1H), 1.92-2.08 (m, 1H),2.12-2.24 (m, 1H), 2.31-2.42 (m, 1H), 2.43-2.55 (m, 1H), 2.68-2.81 (m,1H), 2.84-2.94 (m, 2H), 2.96-3.06 (m, 2H), 3.33 (s, 3H), 3.83 (t, 2H,J=4.8 Hz), 4.16 (d, 1H, J=16.5 Hz), 4.35 (d, 1H, J=16.5 Hz), 4.4-4.44(m, 3H), 7.49 (d, 1H, J=1.8 Hz), 7.51 (d, 1H, J=1.8 Hz), 7.86 (dd, 1H,J=7.8, 6.0 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.60 (d, 1H, J=5.7 Hz). ¹³C NMR(D₂O) δ 20.2, 20.5, 25.1, 25.4, 27.7, 39.6, 46.8, 47.9, 51.7, 59.0,60.3, 70.5, 119.3, 123.3, 125.9, 139.4, 140.6, 145.6, 148.1, 151.3.ES-MS m/z 358 (M+H). Anal. Calcd. for C₂₀H₃₁N₅O.3.1HBr.1.4H₂O.0.2C₄H₁₀O:C, 38.34; H, 6.02; N, 10.75; Br 38.02. Found: C, 38.59; H, 5.93; N,10.77; Br 37.63.

Example 129

COMPOUND 129:N¹-(4-methyl-1-propyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of 1-allyl-4-methyl-1H-imidazole

4-Methylimidazole (2.0g, 24.36 mmol), allyl bromide (2.2 mL, 24.36mmol), N,N-diisopropylethylamine (5.0 mL, 29.24 mmol) in DMF (50 mL)were stirred at 80° C. overnight. Then the reaction mixture was cooled,quenched with saturated NaHCO₃ (30 mL), and extracted with CH₂Cl₂ (4×40mL). The combined organic layers were dried (MgSO₄), filtered,concentrated, and dried in vacuo to afford a brown oil. Purification byflash column chromatography on silica using 2% CH₃OH/CH₂Cl₂ afforded theproduct as a yellow oil (1.13 g, 40%). ¹H NMR (CDCl₃) (as a mixture ofregio-isomers) δ 2.17 and 2.22 (s, total 3H), 4.44-4.48 (m, total 2H),5.19-5.24 (m, total 2H), 5.89-6.00 (m, total 1H), 6.61 and 6.79 (s,total 1H), 7.35 and 7.39 (s, total 1H).

Preparation of 1-allyl-4-methyl-1H-imidzaole-2-carbaldehyde

To a solution of the above imidazole (1.23 g, 10.07 mmol) in THF (40 mL)at −78° C. and under Ar(g), was added n-butyllithium (2.5 M in hexanes).After 45 minutes, DMF was added dropwise the reaction mixture wasstirred at room temperature for 1 hour. Then it was quenched withsaturated NH₄Cl (20 mL) and the solvent was removed under reducedpressure. The residue was dissolved in CH₂Cl₂ (20 mL) and water (10 mL)and the phases were separated. The aqueous layer was washed twice withCH₂Cl₂ (25 mL). The organic layer was dried (Na₂—SO₄), filtered,concentrated, and dried in vacuo to afford a yellow oil. Purification byflash column chromatography on silica gel using 2% CH₃OH/CH₂Cl₂ affordedthe product as a yellow oil (575 mg, 38%). ¹H NMR (CDCl₃) (as a mixtureof regio-isomers) δ 2.26 and 2.30 (s, total 3H), 4.96-5.25 (m, total4H), 5.91-5.97 (m, total 1H), 6.74 and 6.92 (m, total 1H), 9.70 and 9.73(s, total 1H).

Preparation of2-{4-[(1-allyl-4-methyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione

To a solution of the above aldehyde (268 mg, 1.773 mmol) and2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione(743 mg, 2.13 mmol) in CH₂Cl₂ (17 mL) was added sodiumtriacetoxyborohydride (752 mg, 3.55 mmol). The reaction mixture wasstirred at room temperature overnight. Then it was extracted withsaturated NaHCO₃ (3×20 mL). The organic layer was dried (MgSO₄),filtered, concentrated, and dried in vacuo to afford a yellow foam.Purification by flash column chromatography on silica gel using 10%CH₃OH/ethyl acetate afforded the product as a pale yellow foam (263 mg,31%). ¹H NMR (CDCl₃) (as a mixture of regio-isomers) δ 1.52-1.60 (m,total 4H), 1.89-2.11 (m, total 8H), 2.56-2.66 (m, total 4H), 2.55 (t,2H, J=7.5 Hz), 3.76 (d, 2H, J=6.0 Hz), 3.99 (t, 1H, J=6.0 Hz), 4.84-4.90(m, total 1H) 4.93 and 4.96 (s, total 1H), 5.03-5.06 (m, total 2H),5.83-5.87 (m, 1H), 6.43 (s, 1H), 6.99 (dd, 1H, J=3.0 Hz), 7.27 (d, 1H,J=6.0 Hz), 7.68-7.70 (m, 2H), 7.80-7.82 (m, 2H), 8.39 (d, 1H, J=3.0 Hz).

Preparation ofN¹-(4-methyl-1-propyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine

To a solution of the above amine (263 mg, 0.54 mmol) in ethanol (10 mL)was added hydrazine hydrate (0.13 mL, 2.72 mmol). The reaction mixturewas stirred at room temperature for 3 days. Then the solvent was removedunder reduced pressure. Purification by radial chromatography on silicagel (2 mm plate; using NH₄OH/CH₃OH/CH₂Cl₂; 1:4:100→1:6:100) afforded ayellow oil, which the ¹H NMR indicated as a mixture of the allyl productand the n-propyl product.

The above amine (150 mg, 0.31 mmol) in methanol (15 mL) was hydrogenatedat 40 psi in the presence of palladium/carbon (15 mg) overnight. Thenthe reaction mixture was filtered through a layer of celite and thefiltrated was concentrated down to dryness to afford a yellow oil.Purifcation by radial chromatography (1 mm plate; usingNH₄OH/CH₃OH/CH⁻²Cl₂; 1:4:100→1:7:100) afforded the product as a yellowoil (67 mg, 61%). ¹H NMR (CDCl₃) δ 0.83 (t, 3H, J=7.5 Hz), 1.59-1.69 (m,3H), 1.97-2.02 (m, 4H), 2.13 (s, 3H), 2.53-2.70 (m, 8H), 3.72 (d, 2H),3.87-3.92 (m, 1H), 4.03-4.07 (m, 2H), 6.50 (s, 1H), 7.04 (d, 1H, J=3.0Hz), 7.34 (d, 1H, J=9.0 Hz), 8.50 (d, 1H, J=6.0 Hz).

Preparation ofN¹-(4-methyl-1-propyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of the above amine (67 mg, 0.19 mmol) in acetic acid (2mL) was added hydrobromide saturated acetic acid (2 mL). The reactionmixture was stirred for 30 minutes. Then it was triturated with diethylether three times and the precipitate was dried in vacuo. The solid wasre-dissolved in anhydrous methanol (0.5 mL) and was triturated withdiethyl ether three times to afford a yellow solid (40 mg, 32%). ¹H NMR(D₂O) δ 0.89 (t, 3H, J=7.5 Hz), 1.51 (br s, 4H), 1.80 (q, 3H, J=7.5 Hz0,1.97-2.01 (m, 1H), 2.16-2.20 (m, 1H), 2.31-2.35 (m, 4H), 2.49 (br m,1H), 2.71-2.76 (m, 1H), 2.88-2.90 (m, 2H), 2.99-3.01 (m, 2H), 4.06 (t,3H, J=6.9 Hz), 4.27 (d, 1H, J=16.8 Hz), 4.38-4.43 (m, 1H), 7.14 (s, 1H),7.87 (t, 1H, J=6.3 Hz), 8.35 (d, 1H, J=7.8 Hz), 8.59 (d, 1H, J=5.4 Hz).¹³C NMR (D₂O) δ 9.40, 10.39, 20.24, 20.42, 23.27, 25.08, 25.42, 27.66,39.55, 46.43, 49.39, 51.59, 60.27, 119.71, 125.90, 129.96, 139.27,140.56, 143.47, 148.08, 151.38. ES-MS m/z 356 [M+H]⁺. Anal. Calcd. forC₂₁H₃₃N₅. 3.0HBr.2.0H₂O.0.3C₄H₁₀O: C, 40.61; H, 6.60; N, 10.67; Br,36.51. Found: C, 4.35; H, 6.35; N, 10.43; Br, 36.39.

Example 130

COMPOUND 130: Preparation ofN¹-(1-propyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of 2-Imidazolecarboxaldehyde (0.81 g, 8.4 mmol) anddiisopropylethylamine (2.2 mL, 12.6 mmol) in anhydrous DMF (28 mL) wasadded allyl bromide (0.88 mL, 10.1 mmol) and the solution was stirred at60° C. for 16 hours. The mixture was then concentrated under reducedpressure and the residue partitioned between dichloromethane (20 mL) andsodium bicarbonate (15 mL). The organic phase was separated and theaqueous phase was extracted with dichloromethane (2×15 mL). The combinedorganic phases were then dried (Na₂SO₄), filtered, and concentratedunder reduced pressure to give a crude residue that was purified bycolumn chromatography with silica gel (1:99 MeOH/CH₂Cl₂). This afforded2-(N-allylimidazole)-carboxaldehyde (0.62 g, 54%). ¹H NMR (CDCl₃) δ 5.02(d, 2H, J=6.0 Hz), 5.10 (d, 1H, J=18.0 Hz), 5.25 (d, 1H, J=9.0 Hz), 5.96(m, 1H), 7.16 (s, 1H), 7.30 (s, 1H), 9.81 (s, 1H).

Using general procedure B,2-[4-(5,6,7,8-Tetrahydroquinolin-8-ylamino)-butyl]-isoindole-1,3-dione(0.80 g, 2.3 mmol), 2-(N-allylimidazole)-carboxaldehyde (0.62 g, 4.5mmol) and sodium triacetoxyborohydride (1.16 g, 5.5 mmol) were stirredat room temperature in dichloromethane (22 mL) for 16 hours to yield,after work-up and column chromatography (1:4 ethyl acetate:hexane),2-{4-[(1-Allyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-isoindole-1,3-dioneas a yellow oil (0.45 g, 40%). ¹H NMR (CDCl₃) δ 1.26 (m, 2H), 1.50-1.70(m, 3H), 1.75-2.00 (m, 1H), 2.03 (m, 2H), 2.54 (m, 2H), 2.57-2.80 (m,2H), 3.55 (t, 2H, J=6.0 Hz), 3.83 (s, 2H), 3.97 (m, 1H), 4.84 (d, 1H,J=15.0 Hz), 4.92 (d, 1H, J=15.0 Hz), 5.07 (br d, 2H, J=7.5 Hz), 5.93 (m,1H), 6.77 (s, 1H), 6.82 (s, 1H), 7.01 (m, 1H), 7.30 (d, 1H, J=7.0 Hz),7.70 (m, 2H), 7.82 (m, 2H), 8.40 (d, 1H, J=3.0 Hz).

A solution of the above compound (0.45 g, 0.96 mmol) in anhydrousethanol (10 mL) was treated with hydrazine monohydrate (0.50 mL, 9.6mmol) and stirred for 16 h. The white mixture was then filtered,concentrated under reduced pressure, and purified by columnchromatography with silica gel (10:1:84 methanol:ammoniumhydroxide:dichloromethane) to give a mixture of N-propyl andN-allylimidazole products. (0.19 g, 58%).

The material from above (0.19 g) was dissolved in anhydrous methanol(5.6 mL) and the reaction vessel purged with nitrogen. 10% palladium oncarbon (40 mg) was added and the mixture stirred under an atmosphere ofhydrogen (30 psi) for 16 hours. The reaction mixture was then filteredthrough celite and the solvent removed under reduced pressure. The crudematerial was then diluted with ethyl acetate (20 mL) and washed withbrine (4×15 mL) to remove DMF. The organic phase was then dried(Na₂SO₄), filtered, and concentrated under reduced pressure to give aresidue that was purified by column chromatography with silica gel(5:1:94 methanol:ammonium hydroxide:dichloromethane). This affordedN-(1-propyl-1H-imidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine(67 mg, 35%). ¹H NMR (CDCl₃) δ 0.84 (t, 3H, J=7.5 Hz), 1.40 (br, 4H),1.67 (m, 3H), 1.80-2.05 (m, 3H), 2.50-2.85 (m, 6H), 3.31 (br, 2H, NH),3.78 (s, 2H), 3.96 (m, 1H), 4.07 (m, 1H), 4.14 (m, 1H), 6.81 (s, 1H),6.89 (s, 1H), 7.06 (m, 1H), 7.35 (d, 1H, J=6.0 Hz), 8.51 (d, 1H, J=6.0Hz).

Using general procedure D: The above material (67 mg, 0.19 mmol) wasconverted to the hydrobromide salt to provide COMPOUND 130 (108 mg) as awhite solid. ¹H NMR (D₂O) δ 0.90 (t, 3H, J=7.4Hz), 1.50 (br, 4H), 1.81(m, 3H), 2.04 (m, 1H), 2.17 (br m, 1H), 2.36 (br m, 1H), 2.48 (br m,1H), 2.75 (br m, 1H), 2.89 (br, 2H), 3.00 (br, 2H), 4.10-4.18 (m, 3H),4.34 (d, 1H, J=16.8 Hz), 4.40 (m, 1H), 7.47 (s, 2H), 7.86 (t, 2H, J=7.0Hz), 8.34 (d, 1H, J=8.1 Hz), 8.59 (d, 1H, J=5.7 Hz). ¹³C NMR (D₂O) δ10.43, 20.30, 20.42, 23.28, 25.08, 25.42, 27.68, 39.56, 46.60, 49.72,51.63, 60.36, 119.11, 123.29, 125.93, 139.35, 140.59, 144.68, 148.12,151.28. ES-MS m/z 342 (M+H). Anal. Calcd. forC₂₀H₃₁N₅.3.5HBr.1.9H₂O.0.3C₄H₁₀O: C, 37.38; H, 6.11; N, 10.28; Br,41.06. Found: C, 37.43; H, 5.86; N, 10.28; Br, 40.90.

Example 131

COMPOUND 131:N¹-(1-methyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)butane-1,4-diamine(hydrobromide salt) Preparation of2-{4-[(1-methyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione

To a solution of2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylaminol)-butyl]-isoindol-1,3-dione(190 mg, 0.544 mmol) and 1-methyl-2-imidazolecarboxaldehyde (54 mg, 0.49mmol) in CH₂Cl₂ (2.5 mL) was added sodium triacetoxyborohydride (209 mg,0.99 mmol). It was then diluted with CH₂Cl₂ (15 mL) and extracted withsaturated NaHCO₃ (2×15 mL). The organic layer was dried (MgSO₄),filtered, concentrated, and dried in vacuo to afford a yellow oil.Purification by radial chromatography on silica gel (2 mm plate, usingNH₄OH/CH₃OH/CH₂Cl₂; 1:1:100→1:3:100, gradient elution) afforded thedesired product as a yellow oil (160 mg, 73%). ¹H NMR (CDCl₃) δ1.24-1.31 (m, 2H), 1.51-1.66 (m, 2H), 1.84-2.07 (m, 3H), 2.53-2.76 (m,5H), 3.54 (t, 2H, J=7.2 Hz), 3.77 (2, 3H), 3.74 (d, 2H, J=15.9 Hz), 3.97(t, 1H, J=9.0 Hz), 6.73 (s, 1H), 6.77 (s, 1H), 6.99 (dd, 1H, J=7.5, 4.8Hz), 7.30 (d, 1H, J=7.5 Hz), 7.68-7.72 (m, 2H), 7.78-7.84 (m, 2H), 8.40(d, 1H, J=3.9 Hz).

Preparation ofN¹-(1-methyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quionlin-8-yl)-butane-1,4-diamine

To a solution of the above amine (152 mg, 0.34 mmol) in ethanol (8 mL)was added hydrazine hydrate (83 μL, 1.71 mmol). The reaction mixture wasstirred overnight. Then the solvent was removed under reduced pressureto afford a yellow solid. Purification by radial chromatography onsilica gel (1 mm plate, using NH₄OH/CH₃OH/CH₂Cl₂; 1:3:100→1:6:100,gradient elution) afforded the desired product as a yellow oil (48 mg,47%). ¹H NMR (CDCl₃) δ 1.33-1.35 (br s, 2H), 1.64-1.67 (m, 1H),1.87-2.05 (m, 3H), 2.52-2.77 (m, 6H), 3.43 (s, 2H), 3.71 (s, 3H), 3.81(s, 2H), 4.00 (t, 1H, J=7.4 Hz), 6.76 (s, 1H), 6.84 (s, 1H), 7.03 (dd,1H, J=7.7, 4.8 Hz), 7.33 (d, 1H, J=7.5 Hz), 8.44 (d, 1H, J=4.5 Hz),

Preparation ofN¹-(1-methyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quionlin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of the above amine (48 mg, 0.015 mmol) in acetic acid (3mL) was added hydrobromic acid saturated acetic acid (2 mL) and thereaction mixture was stirred for 30 minutes. Then it was triturated withdiethyl ether three times to afford a white solid. The solid wasdissolved in methanol (1 mL) and was triturated with diethyl ether threetimes to afford COMPOUND 131 as a white solid (72 mg, 79%). ¹H NMR (D₂O)δ 1.52-1.55 (m, 4H), 1.75-1.89 (m, 1H), 2.01 (q, 1H, J=13.2 Hz),2.15-2.21 (m, 1H), 2.36-2.39 (m, 1H), 2.49-2.55 (m, 1H), 2.74-2.82 (m,1H), 2.89-2.91 (m, 2H), 3.00-3.03 (m, 2H), 3.83 (s, 3H), 4.22 (ABq, 2H,J=53.9, 16.8 Hz), 4.42 (dd, 1H, J=9.0, 5.4 Hz), 7.42 (ABq, 2H, J=12.9,2.1 Hz), 7.86 (dd, 1H, J=8.1, 6.0 Hz), 8.35 (d, 1H, J=8.1 Hz), 8.59 (d,1H, J=5.1 Hz). ¹³C NMR (D₂O) δ 20.29, 20.43, 25.08, 25.36, 27.67, 34.73,39.56, 46.37, 51.71, 60.28, 118.73, 124.50, 125.90, 139.35, 140.60,144.98, 148.10, 151.33. ES-MS m/z 314 [M+H]⁺. Anal. Calcd. forC₁₈H₂₇N₅-.3.0HBr.2.1H₂O: C, 36.40; H, 5.80; N, 11.79; Br, 40.35. Found:C, 36.28; H, 5.78; N, 11.48; Br, 40.66.

Example 132

COMPOUND 132: Preparation ofN¹-(1-allyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine(hydrobromide salt)

To a solution of 2-Imidazolecarboxaldehyde (0.81 g, 8.4 mmol) anddiisopropylethylamine (2.2 mL, 12.6 mmol) in anhydrous DMF (28 mL) wasadded allyl bromide (0.88 mL, 10.1 mmol) and the solution was stirred at60° C. for 16 hours. The mixture was then concentrated under reducedpressure and the residue partitioned between dichloromethane (20 mL) andsodium bicarbonate (15 mL). The organic phase was separated and theaqueous phase was extracted with dichloromethane (2×15 mL). The combinedorganic phases were then dried (Na₂SO₄), filtered, and concentratedunder reduced pressure to give a crude residue that was purified bycolumn chromatography with silica gel (1:99 MeOH/CH₂Cl₂). This afforded2-(N-allylimidazole)-carboxaldehyde (0.62 g, 54%). ¹H NMR (CDCl₃) δ 5.02(d, 2H, J=6.0 Hz), 5.10 (d, 1H, J=18.0 Hz), 5.25 (d, 1H, J=9.0 Hz), 5.96(m, 1H), 7.16 (s, 1H), 7.30 (s, 1H), 9.81 (s, 1H).

Using general procedure B,2-[4-(5,6,7,8-Tetrahydroquinolin-8-ylamino)-butyl]-isoindole-1,3-dione(0.80 g, 2.3 mmol), 2-(N-allylimidazole)-carboxaldehyde (0.62 g, 4.5mmol) and sodium triacetoxyborohydride (1.16 g, 5.5 mmol) were stirredat room temperature in dichloromethane (22 mL) for 16 hours to yield,after work-up and column chromatography (1:4 ethyl acetate:hexane),2-{4-[(1-Allyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-isoindole-1,3-dioneas a yellow oil (0.45 g, 40%). ¹H NMR (CDCl₃) δ 1.26 (m, 2H), 1.50-1.70(m, 3H), 1.75-2.00 (m, 1H), 2.03 (m, 2H), 2.54 (m, 2H), 2.57-2.80 (m,2H), 3.55 (t, 2H, J=6.0 Hz), 3.83 (s, 2H), 3.97 (m, 1H), 4.84 (d, 1H,J=15.0 Hz), 4.92 (d, 1H, J=15.0 Hz), 5.07 (br d, 2H, J=7.5 Hz), 5.93 (m,1H), 6.77 (s, 1H), 6.82 (s, 1H), 7.01 (m, 1H), 7.30 (d, 1H, J=7.0 Hz),7.70 (m, 2H), 7.82 (m, 2H), 8.40 (d, 1H, J=3.0 Hz).

A solution of the above compound (0.40 g, 0.85 mmol) in anhydrousethanol (8.4 mL) was treated with n-butylamine (0.85 mL, 8.5 mmol) andstirred for 16 h at 80° C. The solution was then concentrated underreduced pressure and purified by column chromatography with silica gel(2:1:97 methanol:ammonium hydroxide:dichloromethane) to giveN-(1-allyl-1H-imidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine.(0.19 g, 66%). ¹H NMR (CDCl₃) δ 1.35 (br, 4H), 1.67 (m, 1H), 1.80-2.10(m, 3H), 2.55 (br, 4H), 2.62-2.80 (m, 2H), 3.80 (s, 2H), 4.02 (m, 1H),4.75 (dd, 1H, J=4.5, 18.0 Hz), 4.89 (d, 1H, J=18.0 Hz), 5.05 (dd, 1H,J=4.5, 18.0 Hz), 5.09 (d, 1H, J=18.0 Hz), 5.88 (m, 1H), 6.81 (s, 1H),6.90 (s, 1H), 7.04 (m, 1H), 7.33 (d, 1H, J=6.0 Hz), 8.45 (d, 1H, J=6.0Hz).

Using general procedure D: The above material (180 mg, 0.53 mmol) wasconverted to the hydrobromide salt to provide COMPOUND 132 (312 mg) as awhite solid. ¹H NMR (D₂O) δ 1.53 (br, 5H), 1.81 (br m, 1H), 1.96 (m,1H), 2.18 (br m, 1H), 2.34 (br m, 1H), 2.48 (br m, 1H), 2.74 (br m, 1H),2.89 (br, 2H), 3.00 (br, 2H), 4.14 (d, 1H, J=16.8 Hz), 4.32 (d, 1H,J=16.5 Hz), 4.38 (m, 1H), 4.85 (br d, 2H, J=5.1 Hz), 5.18 (d, 1H, J=17.1Hz), 5.40 (d, 1H, J=10.5 Hz), 6.02 (m, 1H), 7.48 (d, 1H, J=1.8 Hz), 7.51(d, 1H, J=1.8 Hz), 7.87 (t, 2H, J=6.8 Hz), 8.35 (d, 1H, J=7.8 Hz), 8.60(d, 1H, J=5.7 Hz). ¹³C NMR (D₂O) δ 20.23, 20.39, 25.0 25.39, 27.66,39.57, 46.51, 50.32, 51.57, 60.32, 119.20, 119.92, 123.65, 125.95,131.00, 139.35, 140.60, 145.01, 148.14, 151.27. ES-MS m/z 340 (M+H).Anal. Calcd. for C₂₀H₂₉N₅.3.0HBr.1.6H₂O: C, 39.31; H, 5.81; N, 11.46;Br, 39.23. Found: C, 39.54; H, 5.80; N, 11.07; Br, 39.13.

Example 133

COMPOUND 133: Preparation ofN¹-(5,6,7,8-Tetrahydro-imidazo[1-5-a]pyridin-3-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of5,6,7,8-Tetrahydro-imidazo[1,5-a]pyridine-3-carbaldehyde

To a solution of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine (prepared asdescribed by Lattrell, R. et al. The J. of Antibiotics 1988, 41,1395-1408) in THF (7 mL) at −78° C. was added a solution of n-BuLi (2.5M in hexanes, 0.70 mL, 1.75 mmol) and the reaction stirred at −78° C.for 10 min. DMF (1.0 mL) was added to the mixture at −78° C. and thereaction warmed to room temperature and stirred for 2 h before quenchingwith saturated aqueous NH₄Cl (5 mL). The mixture was diluted with EtOAc(30 mL) and brine and the organic phase washed with brine (1×30 mL),dried (Na₂SO₄) and concentrated in vacuo. The resultant brown oil (191mg) was purified by column chromatography on silica gel (CH₂Cl₂/MeOH,96:4) to afford the desired aldehyde (105 mg, 40%) as an orange oil. ¹HNMR (CDCl₃) δ 1.83-1.89 (m, 2H), 1.94-2.02 (m, 2H), 2.85 (t, 2H, J=6Hz), 4.39 (t, 2H, J=6 Hz), 7.05 (s, 1H), 9.71 (s, 1H).

Following General Procedure B: To a stirred solution of2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(174 mg, 0.50 mmol) and5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine-3-carbaldehyde (82 mg, 0.48mmol) in dry CH₂C1₂ (7 mL) was added NaBH(OAc)₃ (152 mg, 0.72 mmol) andthe mixture stirred at room temperature for 5.5 h. The resultant yellowfoam (271 mg) was purified by column chromatography on silica gel(CH₂Cl₂/MeOH/NH4OH, 96:4:0 then 92:8:0 then 94:4:2) to afford thedesired amine (153 mg, 66%) as a white foam.

To a solution of the phthalimide from above (153 mg, 0.32 mmol) in EtOH(4 mL) was added anhydrous hydrazine (0.055 mL, 1.73 mmol) and themixture stirred overnight. The resultant white solid was filteredthrough filter paper, washing thoroughly with CH₂Cl₂ and the filtrateconcentrated in vacuo. The crude product was purified by radialchromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH, 50:1:1 then20:1:1 then 10:1:1 to give the desired free amine (72 mg, 64%) as a paleyellow oil.

Using General Procedure D: Conversion of the material from above (72 mg,0.20 mmol) to the hydrobromide salt gave COMPOUND 133 (106 mg, 78%) as ayellow solid. ¹H NMR (D₂O) δ 1.48-1.60 (m, 4H), 1.75-1.87 (m, 3H),1.96-2.07 (m, 3H), 2.16-2.20 (m, 1H), 2.34-2.38 (m, 1H), 2.49-2.55 (m,1H), 2.74-2.83 (m, 3H), 2.89-2.95 (m, 2H), 2.99-3.02 (m, 2H), 4.06-4.13(m, 3H), 4.24 (d, 1H, J=16.8 Hz), 4.42 (dd, 1H, J=10.5, 5.4 Hz), 7.14(s, 1H), 7.85 (dd, 1H, J=7.8, 6 Hz), 8.33 (d, 1H, J=7.8 Hz), 8.58 (d,1H, J=5.7 Hz); ¹³C NMR (D₂O) δ 18.77, 20.19, 20.42, 21.77, 25.10, 25.39,27.68, 39.59, 44.44, 46.04, 51.84, 60.13, 114.38, 125.85, 132.38,139.32, 140.57, 142.58, 148.04, 151.44. ES-MS m/z 354 (M+H). Anal.Calcd. for C₂₁H₃₁N₅.3.3HBr.0.9H₂O0.4C₄H₁₀O: C, 40.73; H, 6.07; N, 10.51;Br, 39.57. Found: C, 40.48; H, 5.71; N, 10.34; Br, 39.83.

Example 134

COMPOUND 134: Preparation ofN¹-(4-Methoxymethyl-1H-imidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(hydrobromide salt) Preparation of 4(and3)-Methoxymethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde

To a solution of 4-(hydroxymethyl)imidazole hydrochloride (578 mg, 4.30mmol) in DMF (3.5 mL) was added DIPEA (1.9 mL, 10.9 mmol) and2-(trimethylsilyl)ethoxymethyl chloride (0.83 mL, 4.69 mmol) and themixture stirred overnight. The reaction was diluted with EtOAc (60 mL)and brine (40 mL) and the organic layer washed with brine (2×40 mL),dried (Na₂SO₄) and concentrated. The resultant yellow oil (1.04 g) waspurified by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,96:4:0 then 94:4:2 then 88:10:2) to afford the desired SEM-protectedimidazole (416 mg, 42%) as a mixture of regioisomers.

To a solution of the alcohol from above (416 mg, 1.82 mmol) in THF (10mL) at 0° C. was added NaH and the mixture stirred for 30 min. To theresultant suspension was added MeI and the reaction stirred from 0° C.to room temperature over 2.5 h before diluting with H2O (20 mL) andEtOAc (25 mL). The organic phase was washed with brine (1×25 mL), dried(Na₂SO₄) and concentrated to afford the desired methyl ether (430 mg) asa yellow oil.

To a solution of the imidazole from above (430 mg, 1.78 mmol) in THF (10mL) at −78° C. was added a solution of n-BuLi (2.5 M in hexanes, 0.71mL, 1.78 mmol) and the reaction stirred at −78° C. for 10 min. DMF (1.0mL) was added to the mixture at −78° C. and the reaction warmed to roomtemperature and stirred for 2 h before quenching with saturated aqueousNH₄Cl (10 mL). The mixture was diluted with EtOAc (30 mL) and brine (20mL) and the organic phase washed with brine (1×30 mL), dried (Na₂SO₄)and concentrated in vacuo. The resultant yellow oil was purified bycolumn chromatography on silica gel (Hexanes/EtOAc, 2:1) to afford amixture of the desired two regioisomeric aldehydes (194 mg, 40%) as ayellow oil. ¹H NMR (CDCl₃) δ 1.83-1.89 (m, 2H), 1.94-2.02 (m, 2H), 2.85(t, 2H, J=6 Hz), 4.39 (t, 2H, J=6 Hz), 7.05 (s, 1H), 9.71 (s, 1H).

Following General Procedure B: To a stirred solution of2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione(269 mg, 0.77 mmol) and 4(and3)-methoxymethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde(194 mg, 0.72 mmol) in dry CH₂Cl₂ (8 mL) was added NaBH(OAc)₃ (236 mg,1.11 mmol) and the mixture stirred at room temperature for 4 h. Theresultant crude brown oil (459 mg) was purified by column chromatographyon silica gel (CH₂Cl₂/MeOH, 96:4) to afford the desired amine (329 mg,76%) as a pale yellow oil.

A solution of the SEM-protected imidazole (329 mg, 0.55 mmol) in 4 N HCl(8 mL) was stirred at 60° C. for 4.5 h then cooled to room temperatureand neutralized with solid K₂CO₃ (8.1 g). The slurry was diluted withH₂O (15 mL) and CH₂Cl₂ (30 mL) and the aqueous phase extracted withCH₂Cl₂ (3×30 mL). The combined organic layers were dried (Na₂SO₄),concentrated and purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 96:4 then 92:8) to afford the desired product (248 mg,96%) as a clear oil.

To a solution of the phthalimide from above (248 mg, 0.52 mmol) in EtOH(4 mL) was added anhydrous hydrazine (0.10 mL, 3.15 mmol) and themixture stirred overnight. The resultant white solid was filteredthrough filter paper, washing thoroughly with CH₂Cl₂ and the filtrateconcentrated in vacuo. The crude product was purified by radialchromatography on silica gel (1 mm plate, CH₂Cl_(2/)MeOH/NH₄OH, 50:1:1then 25:1:1 then 10:1:1) to give the desired free amine (83 mg, 46%) asa clear oil.

Using General Procedure D: Conversion of the material from above (83 mg,0.18 mmol) to the hydrobromide salt gave COMPOUND 134 (137 mg, 88%) as awhite solid. ¹H NMR (D₂O) δ 1.44-1.55 (m, 4H), 1.79-2.01 (m, 2H),2.14-2.18 (m, 1H), 2.26-2.31 (m, 1H), 2.43-2.53 (m, 1H), 2.72-2.79 (m,1H), 2.88-2.92 (m, 2H), 2.98-3.01 (m, 2H), 3.40 (s, 3H), 4.16 (d, 1H,J=16.2 Hz), 4.29 (d, 1H, J=16.2 Hz), 4.42 (dd, 1H, J=10.5, 5.4 Hz), 4.58(s, 2H), 7.47 (s, 1H), 7.86 (dd, 1H, J=7.8, 6 Hz), 8.34 (d, 1H, J=7.8Hz), 8.59 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ 20.33, 20.46, 25.08, 25.37,27.63, 39.59, 47.43, 51.36, 58.23, 60.30, 63.39, 118.68, 125.90, 129.93,139.28, 140.51, 146.34, 148.04, 151.45. ES-MS m/z 344 (M+H). Anal.Calcd. for C₁₉H₂₉N₅O.3.2HBr.0.7H₂O.0.4C₄H₁₀O: C, 38.38; H, 5.88; N,10.86; Br, 39.66. Found: C, 38.42; H, 5.75; N, 10.92; Br, 39.56.

Example 135

COMPOUND 135: Preparation ofN¹-(1-Allyl-1H-imidazol-2-ylmethyl)-N¹-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine(Hydrochloride salt) Preparation of 1-Allyl-1H-imidazole-2-carbaldehyde

A solution of 2-imidazole carboxaldehyde (15.0 g, 156 mmol), allylbromide (22.6g, 187 mmol) and diisopropylethylamine (40.7 mL, 234 mmol)was stirred in N,N-dimethylformamide (500 mL) for 23 hours. The solventwas removed under reduced pressure and the residue was dissolved indichloromethane (370 mL). The solution was washed once with a saturatedsolution of sodium carbonate (185 mL). The layers were separated and theaqueous layer was extracted with dichloromethane (2×280 mL). Thecombined organic portions were dried with sodium sulfate, filtered andconcentrated under reduced pressure to afford a yellow oil. The crudematerial was then purified by flash chromatography (99:1CH₂Cl₂/methanol) to provide the desired compound (12.8 g, 60%) as yellowoil. ¹H NMR (300 MHz, CDCl₃, δ ppm) 5.04 (d, 2H, J=5.5 Hz), 5.11 (d, 1H,J=17.5 Hz), 5.25 (d, 1H, J=10.0 Hz), 5.90-6.05 (m, 1H), 7.16 (s, 1H),7.30 (s, 1H), 9.81 (s, 1H); ¹³C NMR (75 MHz, CDCl₃, δ ppm) 49.77,118.61, 126.00, 131.74, 132.39, 143.17, 182.05.

Preparation ofN¹-(1-Allyl-1H-imidazol-2-ylmethyl)-N¹-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine(COMPOUND 135)

Using general procedure B: Reaction ofN′-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine (29.86 g, 85mmol) and 1-Allyl-1H-imidazole-2-carbaldehyde (12.8 g, 94 mmol) withNaBH(OAc)₃ (18.0 g, 85 mmol) in CH₂Cl₂ (470 mL) for 39 hours followed bypurification of the crude material by flash chromatography (4:1AcOEt/hexane) provided 21 g of a yellow oil. ¹H NMR (300 MHz, CDCl₃, δppm) 3.55 (t, 2H, J=7.0 Hz), 1.20-2.80 (series of m, 12H), 3.84 (s, 2H),3.98 (m, 1H), 4.87 (dd, 1H, J=1.0 & 17.0 Hz), 4.70-5.15 (m, 2H), 5.08(dd, 1H, J=1.0 & 10.0 Hz), 5.80-6.00 (m, 1H), 6.76 (d, 1H, J=1.0 Hz),6.82 (d, 1H, J=1.0 Hz), 7.00 (dd, 1H, J=4.5 & 7.5 Hz), 7.31 (d, 1H,J=7.5 Hz), 7.65-7.75 (m, 2H), 7.75-7.85 (m, 2H), 8.41 (d, 1H, J=4.5 Hz).

The2-{4-[(S)-(1-Allyl-1H-imidazol-2-ylmethyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-isoindole-1,3-dione(21g, 45 mmol) was dissolved in ethanol (450 mL) and was treated withn-butylamine (44.6 mL, 450 mmol). The solution was stirred at 60° C. for21 hours. The mixture was concentrated under reduced pressure and waspurified by flash chromatography (97:2:1 CH₂Cl₂/methanol/NH₄OH andslowly raised the amount of methanol from 2% to 10%). The cleanestfractions (7.37 g, 77%) were carried through the salting procedure.

Following general procedure D, conversion of the material to hishydrochloride salt and re-precipitation from methanol/diethylether gaveCOMPOUND 135 (7.97 g, 82%) as beige solid. ¹H NMR (300 MHz, D₂O, δ ppm)1.45-1.60 (m, 4H), 1.65-1.85 (m, 1H), 1.85-2.05 (m, 1H), 2.05-2.20 (m,1H), 2.25-2.40 (m, 1H), 2.40-2.55 (m, 1H), 2.65-2.80 (m, 1H), 2.85-2.95(m, 2H), 2.95-3.05 (m, 2H), 4.10 (d, 1H, J=17.0 Hz), 4.28 (d, 1H, 17.0Hz), 4.30-4.40 (m, 1H), 4.80-4.85 (m, 2H), 5.14 (d, 1H, J=17.0 Hz), 5.36(d, 1H, J=10.5 Hz), 5.90-6.10 (m, 1H), 7.46 (d, 1H, J=2.0 Hz), 7.81 (dd,1H, J=5.5 & 8.0 Hz), 8.28 (d, 1H, J=8.0 Hz), 8.57 (d, 1H, J=5.5 Hz); ¹³CNMR ((75 MHz, D₂O, δ ppm) 20.20, 20.40, 25.06, 25.37, 27.66, 39.58,46.50, 50.30, 51.56, 60.29, 119.17, 119.91, 123.62, 125.93, 131.02,139.34, 140.55, 145.01, 148.11, 151.23. ES-MS m/z 340 (M+H). Anal.Calcd. for C₂₀H₂₉N₅.3.2HCl.3H₂O.0.3C₄H₁₀O: C, 47.82; H, 7.80; N, 13.15;Cl, 21.31. Found: C, 47.98; H, 7.60; N, 13.11; Cl, 21.17.

Example 136

COMPOUND 136: Preparation ofN¹-{2-[(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-ethyl}-guanidine(hydrobromide salt)

Using General Procedure B: Reaction ofN-(tert-butoxycarbonyl)-2-amino-acetaldehyde (0.204 g, 1.28 mmol) and(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.284 g, 1.02 mmol) with NaBH(OAc)₃ (0.430g, 2.03 mmol) in CH₂Cl₂ (10mL) provided 0.71 g of a yellow foam. The foam was dissolved in THF (10mL) and treated with 6N hydrochloric acid (10 mL). The resultantsolution was stirred at room temperature overnight. The solution wasneutralized with solid K₂CO₃ (5 g), diluted with water (5 mL) andextracted with CH₂Cl₂ (3×20 mL). The combined organic extracts weredried (Na₂SO₄) and concentrated. Purification of the crude material bycolumn chromatography on silica gel (20:1:1 CH₂Cl₂-CH₃OH-NH₄OH) provided0.205 g (64%) ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamineas a yellow solid. To a solution ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine(0.205 g, 0.64 mmol) in dry THF (6 mL) was added N.N′-bis-(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (TetrahedronLett. 1993, 34, 3389.) (0.201 g, 0.64 mmol) and the resultant mixturewas stirred at room temperature for 18 hours. The mixture wasconcentrated and the resultant oil was purified by column chromatographyon silica gel (40:1:1 CH₂Cl₂—CH₃OH—NH₄OH) and provided 0.267 g (74%) ofN,N′-bis(tert-butoxycarbonyl)-N″-{2-[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-ethyl}-guanidineas a white foam.

Using General Procedure D: Conversion of the white foam (257 mg) to thehydrobromide salt with simultaneous removal of the BOC-protectinggroups, followed by reprecipitation of the intermediate solid frommethanol/ether gave COMPOUND 136 (253 mg, 86%) as a white solid. ¹H NMR(D₂O) δ 1.77-1.87 (m, 1H), 1.97-2.18 (m, 2H), 2.32-2.37 (m, 1H),2.75-2.84 (m, 1H), 2.96-3.10 (m, 3H), 3.19-3.33 (m, 2H), 4.39 (d, 1H,J=16.5 HZ), 4.51-4.57 (m, 2H), 7.58-7.61 (m, 2H), 7.77-7.88 (m, 3H),8.34 (d, 1H, J=8.1 Hz), 8.65 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ 20.33,20.57, 27.71, 39.96, 48.11, 50.17, 60.70, 114.33, 126.03, 126.99,131.28, 139.68, 140.87, 148.18, 150.46, 150.84,; ES-MS m/z 364 (M+H).Anal. Calcd. for C₂₀H₂₅N₇.3.0HBr.1.5H₂O.0.2C₄H₁₀O: C, 38.55; H, 5.13; N,15.13; Br, 36.99. Found: C, 38.54; H, 5.07; N, 15.05; Br, 36.95.

Example 137

COMPOUND 137: Preparation of{4-[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butylamino}-aceticacid methyl ester (hydrobromide salt) Preparation of[(2-Nitro-benzenesulfonyl)-(4-oxo-butyl)-amino]-acetic acid methyl ester

To a solution of 4-amino-1-butanol (555 mg, 6.23 mmol) in THF/saturatedaqueous NaHCO₃ (2:1, 15 mL) at 0° C. was added 2-nitrobenzenesulfonylchloride (1.4492 g, 6.54 mmol) and the reaction stirred overnight. Themixture was diluted with CH₂Cl₂ (40 mL) and saturated aqueous NaHCO₃ (30mL) and the aqueous layer extracted with CH₂Cl₂ (1×30 mL). The combinedorganic extracts were dried (Na₂SO₄) and concentrated in vacuo. Theresultant yellow solid (1.74 g) was washed with Et₂O (3×15 mL) and driedin vacuo to afford the nosyl-protected alcohol (1.34 g, 78%) as a whitesolid.

To a suspension of the alcohol from above (1.34 g, 4.89 mmol) and K₂CO₃(1.346 g, 9.74 mmol) in CH₃CN (20 mL) was added methyl bromoacetate(0.55 mL, 5.81 mmol) and the reaction stirred overnight then at 50° C.for 4 h. The mixture was cooled to room temperature, concentrated,diluted with CH₂Cl₂ (50 mL) and washed with H₂O (40 mL). The aqueouslayer was extracted with CH₂Cl₂ (1×15 mL) and the combined organiclayers dried (Na₂SO₄) and concentrated to afford the alkylated amine(1.59 g) as a pale yellow oil.

A solution of the above alcohol (881 mg, 2.55 mmol) in CH₂Cl₂ (10 mL)was treated with molecular sieves (837 mg), N-methylmorpholine oxide(673 mg, 5.75 mmol), and TPAP (64 mg, 0.18 mmol). The mixture wasstirred for 1.5 hours and then filtered through silica, washing with 1:1EtOAc/hexanes. The filtrate was then concentrated under reduced pressureto afford the title compound (414 mg, 47%) as a pale yellow oil. ¹H NMR(CDCl₃) δ 1.86 (q, 2H, J=6 Hz), 2.57 (t, 2H, J=6 Hz), 3.43 (t, 2H, J=6Hz), 3.65 (s, 3H), 4.17 (s, 2H), 7.59-7.62 (m, 1H), 7.68-7.71 (m, 2H),8.02-8.05 (m, 1H), 9.75 (s, 1H).

Following General Procedure B: To a stirred solution of(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(155 mg, 0.56 mmol) and[(2-nitro-benzenesulfonyl)-(4-oxo-butyl)-amino]-acetic acid methyl ester(189 mg, 0.55 mmol) in dry CH₂Cl₂ (10 mL) was added NaBH(OAc)₃ (159 mg,0.75 mmol) and the mixture stirred at room temperature overnight. Theresultant crude brown oil (0.81 g) was purified by column chromatographyon silica gel (CH₂Cl₂/MeOH/NH₄OH, 95:4:1) to afford the desired amine(166 mg, 48%) as a yellow foam.

To a stirred solution of the nosyl-protected amine from above (125 mg,0.21 mmol) in anhydrous CH₃CN (5 mL) at room temperature, was addedthiophenol (0.12 mL, 1.17 mmol) followed by powdered K₂CO₃ (177 mg, 1.28mmol). The resulting bright yellow solution was stirred at roomtemperature overnight. The solvent was removed under reduced pressureand CH₂Cl₂ (30 mL) and water (30 mL) were added to the residue. Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(2×10 mL). The combined organic phases were dried (Na2SO₄) andconcentrated. Purification of the crude material by columnchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 94:4:2) followed byradial chromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH,100:1:1 the 50:1:1 then 25:1:1) provided the free base (33 mg, 37%) as aclear oil.

Using General Procedure D: Conversion of the material from above (33 mg,0.078 mmol) to the hydrobromide salt gave COMPOUND 137 (43 mg, 78%) as awhite solid. ¹H NMR (D₂O) δ 1.54-1.59 (m, 4H), 1.76-1.90 (m, 1H),1.97-2.09 (m, 1H), 2.16-2.21 (m, 1H), 2.36-2.39 (m, 1H), 2.55-2.61 (m,1H), 2.81-2.88 (m, 1H), 2.99-3.02 (br m, 4H), 3.78 (s, 3H), 3.93 (s,2H), 4.40 (d, 1H, J=16.8 Hz), 4.49-4.57 (m, 1H), 4.54 (d, 1H, J=16.8Hz), 7.60 (dd, 2H, J=6, 3 Hz), 7.80 (dd, 2H, J=6, 3 Hz), 7.87 (dd, 1H,J=7.8, 6 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.64 (d, 1H, J=5.7 Hz); ¹³C NMR(D₂O) δ 20.44, 23.66, 25.38, 27.65, 47.57, 47.62, 48.26, 51.64, 53.85,60.67, 114.27, 125.94, 126.93, 131.00, 139.35, 140.61, 148.11, 151.24,151.77, 168.15. ES-MS m/z 422 (M+H). Anal. Calcd. forC₂₄H₃₁N₅O₂.3.0HBr.2.2H₂O: C, 40.95; H, 5.50; N, 9.95; Br, 34.05. Found:C, 40.91; H, 5.57; N, 9.67; Br, 34.32.

Example 138

COMPOUND 138: Preparation of pyrazine-2-carboxylic acid{4-[(1H-benzimidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-amide

To a solution ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine(211 mg, 0.60 mmol) in CH₂Cl₂ (5 mL) was added 2-pyrazinecarboxylic acid(74.8 mg, 0.60 mmol), N,N-diisopropylethylamine (0.21 mL, 1.2 mmol),HOBT (97.7 mg, 0.72 mmol) and EDC (139 mg, 0.72 mmol). The resultantsolution was stirred at room temperature for 16 h. The reaction mixturewas diluted with CH₂Cl₂ (15 mL) and brine (25 mL) and the phases mixedand separated. The aqueous layer was extracted with CH₂Cl₂ (2×15 mL) andthe combined organic extracts dried (Na₂SO₄), filtered, and concentratedin vacuo. Purification of the crude white foam by flash chromatographyon silica gel (CH₂Cl₂/MeOH/NH₄OH, 100:3:1) gave the title compound (166mg, 60%) as a white foam. ¹H NMR (CDCl₃) δ 1.42-1.80 (m, 7H), 1.86-2.09(m, 2H), 2.16-2.26 (m, 1H), 2.58-2.90 (m, 4H), 3.23-3.37 (m, 2H), 4.13(d, 1H, J=16.8 Hz), 4.04 (d, 1H, J=16.8 Hz), 4.02-4.11 (m, 1H),7.11-7.22 (m, 3H), 7.42 (d, 1H, J=7.5 Hz), 7.46-7.52 (m, 1H), 7.60-7.76(m, 2H), 8.43 (t, 1H, J=1.5 Hz), 8.58 (d, 1H, J=3.9 Hz), 8.71 (d, 1H,J=2.4 Hz), 9.34 (d, 1H, J=1.2 (Hz); ¹³C NMR (CDCl₃) δ 21.76, 24.03,26.20, 27.35, 29.56, 39.38, 49.92, 50.39, 62.15, 111.37, 119.11, 121.91,122.59, 134.98, 137.73, 142.83, 144.64, 144.83, 147.01, 147.47, 156.91,157.84, 163.25; ES-MS m/z 456 (M+H). Anal. Calcd. for C₂₄H₂₅N₇O₂.0.6H₂O: C, 66.96; H, 6.53; N, 21.02. Found: C, 66.94; H, 6.54; N, 21.05.

Example 139

COMPOUND 139: Preparation of Pyridine-2-carboxylic acid{3-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-amide(hydrobromide)

To a stirred solution of picolinic acid (36.7 mg, 0.30 mmol) inanhydrous DMF (3 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.6mmol), HOBT (48.3 mg, 0.36 mmol), EDC (68.6 mg, 0.36 mmol) andN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine(100 mg, 0.30 mmol). The resultant solution was stirred at roomtemperature for 16 h. The reaction mixture was diluted with EtOAc (40mL), brine (15 mL) and H₂O (5 mL) and the two layers mixed vigorouslyfor 15 minutes. The layers were separated and the organic layer washedwith brine (5×15 mL), dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the beige foam by radial chromatography on a 1 mmTLC grade silica gel plate (CH₂Cl₂/MeOH/NH₄OH, 50:1:1) gave the freebase of the title compound (63.0 mg, 48%) as a white foam.

Using General Procedure D: Conversion of the white foam from above (63.0mg, 0.14 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave COMPOUND 139 (81.3 mg,79%) as a cream solid. ¹H NMR (D₂O) δ 1.72-1.92 (m, 3H), 1.93-2.10 (m,1H), 2.11-2.23 (m, 1H), 2.33-2.44 (m, 1H), 2.52-2.64 (m, 1H), 2.83-3.05(m, 3H), 3.24-3.50 (m, 2H), 4.29 (d, 1H, J=16.2 Hz), 4.44 (d, 1H, J=16,5Hz), 4.55 (dd, 1H, J=10.4, 5.7 Hz), 7.42-7.49 (m, 2H), 7.59-7.66 (m,2H), 7.80 (t, 1H, J=6.8 Hz), 7.89 (t, 1H, J=6.5 Hz), 7.95 (d, 1H, J=8.1Hz), 8.24-8.34 (m, 2H), 8.62 (d, 2H J=5.1 Hz); ¹³C NMR (D₂O) δ 20.43,27.63, 37.76, 48.05, 48.93, 59.91, 114.12, 123.82, 125.87, 126.99,129.16, 130.71, 139.39, 140.66, 144.19, 144.86, 145.77, 148.03, 151.25,163.22; ES-MS m/z 441 (M+H). Anal. Calcd. for C₂₆H₂₈N₆O.2.9HBr.2.7 H₂O:C, 43.14; H, 5.05; N, 11.61; Br, 32.01. Found: C, 43.26; H, 5.07; N,11.24; Br, 32.37.

Example 140

COMPOUND 140: Preparation of Isoquinoline-3-carboxylic acid{3-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-amide(hydrobromide)

To a stirred solution of 1-isoquinolinecarboxylic acid (51.6 mg, 0.30mmol) in anhydrous DMF (3 mL) was added N,N-diisopropylethylamine (0.10mL, 0.6 mmol), HOBT (48.3 mg, 0.36 mmol), EDC (68.6 mg, 0.36 mmol) andN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine(100 mg, 0.30 mmol). The resultant solution was stirred at roomtemperature for 16 h. The reaction mixture was diluted with EtOAc (40mL), brine (15 mL) and H₂O (5 mL) and the two layers mixed vigorouslyfor 15 minutes. The layers were separated and the organic layer washedwith brine (5×15 mL), dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the crude material by radial chromatography on aI mm TLC grade silica gel plate (CH₂Cl₂/MeOH/NH₄OH, 50:1:1) gave thefree base of the title compound (79.2 mg, 54%) as a white foam.

Using General Procedure D: Conversion of the white foam from above (79.2mg, 0.16 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave COMPOUND 140 (106 mg,86%) as a yellow solid. ¹H NMR (D₂O) δ 1.76-1.97 (m, 3H), 1.95-2.12 (m,1H), 2.12-2.23 (m, 1H), 2.33-2.45 (m, 1H), 2.57-2.70 (m, 1H), 2.88-3.04(m, 3H), 3.39-3.54 (m, 2H), 4.33 (d, 1H, J=16.5 Hz), 4.48 (d, 1H, J=16.5Hz), 4.57 (dd, 1H, J=10.8, 5.7 Hz), 7.32-7.40 (m, 2H), 7.51-7.60 (m,2H), 7.73-7.83 (m, 2H), 8.02 (t, 1H, J=7.2 Hz), 8.12 (d, 1H, J=6.3 Hz),8.14 (d, 1H, J=7.8 Hz), 8.22 (d, 1H, J=6.3 Hz), 8.27 (d, 1H, J=7.8 Hz),8.36 (d, 1H, J=6.0 Hz), 8.61 (d, 1H J=5.4 Hz); ¹³C NMR (D₂O) δ 20.40,27.66, 38.12, 48.23, 49.24, 60.06, 114.00, 124.73, 125.86, 126.61,126.74, 126.83, 128.43, 130.67, 131.35, 134.81, 135.30, 139.26, 139.41,140.61, 148.07, 149.02, 151.26, 164.46; ES-MS m/z 491 (M+H). Anal.Calcd. for C₃₀H₃₀N₆O.2.9HBr.2.3 H₂O: C, 47.00; H, 4.93; N, 10.96; Br,30.22. Found: C, 47.21; H, 5.01; N, 10.65; Br, 30.06.

Example 141

COMPOUND 141:N-{3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-6-hydroxy-nicotinamide(hydrobromide salt) Preparation of (4-oxo-propyl)-carbamic acidtert-butyl ester

To a solution of oxalyl chloride in CH₂Cl₂ (2.0 M, 12.3 mL, 24.63 mmol)at −78° C. was added DMSO dropwise. The reaction mixture was stirred for20 minutes at −78° C. Then a solution of (4-hydroxy-propyl)-carbamicacid tert-butyl ester (3.32 g, 18.95 mmol) in CH₂Cl₂ (58 mL) was added,followed by triethylamine (13.2 mL, 94.75 mmol), and the reactionmixture was warmed to room temperature. After 1.5 hours, the mixture wasdiluted with brine (50 mL) and the phases were separated. The organiclayer was washed with brine (2×50 mL) and saturated NaHCO₃ (2×50 mL).The combined organic layer was dried (MgSO₄), filtered, concentrated,and dried in vacuo to afford an orange oil (2.76 g, 84%). ¹H NMR (CDCl₃)δ 1.42 (s, 9H), 2.710 (t, 2H, J=6.0 Hz), 3.42 (q, 2H, J=7.5 Hz), 4.90(br s, 1H), 9.80 (s, 1H).

Preparation of2-{[(3-tert-butoxycarbonylamino-propyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester

To a solution of the above aldehyde (1.70 g, 9.82 mmol) and2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzimidazole-1-carboxylicacid tert-butyl ester (3.38 g, 8.92 mmol) in CH₂Cl₂ (20 mL) was addedsodium triacetoxyborohydride (3.78 g, 17.84 mmol). The reaction mixturewas stirred at room temperature for 4 days. Then it was extracted withsaturated NaHCO₃ (3×50 mL). The organic layer was dried (MgSO₄),filtered, concentrated, and dried in vacuo to afford a yellow foam.Purification by flash column chromatography on silica gel using 2%CH₃OH/CH₂Cl₂ afforded the product as a yellow foam (4.23 g, 91%). ¹H NMR(CDCl₃) δ 1.41 (s, 9H), 1.60 (s, 9H), 1.64-1.75 (m, 2H), 1.89-2.04 (m,3H), 2.21-2.25 (m, 1H), 2.66-2.89 (m, 3H), 3.20-3.24 (m, 2H), 3.40-3.44(m, 1H), 4.17-4.43 (m, 3H), 6.90 (d, 1H, J=3.0 Hz), 7.19-7.25 (m, 2H),7.40 (m, 1H), 7.74-7.76 (m, 1h), 7.82-7.84 (m, 1H), 8.35 (d, 1H, J=6.0Hz).

Preparation ofN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine

The above amine (4.23 g, 8.11 mmol) in 3N HCl/THF (2:1) (30 mL) wasstirred at room temperature overnight. Then it was basified to pH=9using potassium carbonate and it was extracted with CHCl₃ (3×50 mL). Thecombined organic layer was dried (Na₂SO₄), filtered, concentrated, anddried in vacuo to afford a yellow foam (2.88 g, 100%). ¹H NMR (CDCl₃) δ1.62-1.79 (m, 3H), 2.09 (m, 1H), 2.42-2.68 (m, 3H), 2.76-2.84 (m, 4H),3.35 (d, 1H, J=12.0 Hz), 4.00 (d, 1H, J=12.0 Hz), 4.10-4.15 (m, 1H),4.34 (d, 1H, J=15.0 Hz), 7.05-7.09 (m, 1H), 7.13-7.16 (m, 2H), 7.39 (d,1H, J=9.0 Hz), 7.60-7.61 (br m, 2H), 8.59 (d, 1H, J=3.0 Hz).

Preparation ofN-[3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-6-hydroxy-nicotinamide

To a solution of the above amine (173 mg, 0.52 mmol) in DMF (3 mL) wasadded 1-hydroxybenzotriazole hydrate (104 mg, 0.77 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148 mg,0.77 mmol), and 6-hydroxynicotinic acid (86 mg, 0.62 mmol). The reactionwas stirred overnight at room temperature. Then it was diluted withethyl acetate (40 mL) and water (25 mL). The organic layer was washedwith saturated NaHCO⁻³ (30 mL) and brine (30 mL), dried (Na₂SO₄),filtered, concentrated, and dried in vacuo to afford a yellow oil.Purification by radial chromatography on silica gel (1 mm plate; usingNH₄—OH/CH₃OH/CH₂Cl₂; 1:2:100→1:10:100) afforded the product as a yellowfoam (63 mg, 27%). ¹H NMR (CDCl₃) δ 1.61-1.88 (m, 4H), 2.01-2.06 (m,1H), 2.20-2.24 (m, 1H), 2.61-2.70 (m, 1H), 2.76-2.85 (m, 3H), 3.26-3.30(m, 1H), 3.45-3.51 (m, 1H), 4.00 (s, 2H), 4.13 (dd, 1H, J=9.0, 6.0 Hz).6.37 (d, 1H, J=9.6 Hz), 7.13-7.18 (m, 3H), 7.43-7.46 (m, 3H), 7.52 (brs, 1H), 7.66 (dd, 1H, J=9.6, 2.4 Hz), 7.91 (d, 1H, J=2.1 Hz), 8.48 (d,1H, J=3.6 Hz).

Preparation ofN-{3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-6-hydroxy-nicotinamide(hydrobromide salt)

To a solution of the above amine (63 mg, 0.14 mmol) in acetic acid (2mL) was added hydrobromide saturated acetic acid (2 mL). The reactionmixture was stirred for 30 minutes. Then it was triturated with diethylether four times to afford the title compound as a white solid (80 mg),which was dried in vacuo. ¹H NMR (D₂O) δ 1.81-2.01 (m, 4H), 2.16-2.20(m, 1H), 2.37-2.41 (m, 1H), 2.50-2.59 (m, 1H), 2.87-2.92 (m, 1H), 3.00(br s, 2H), 3.11-3.16 (m, 1H), 3.37-3.42 (m, 1H), 3.53 (q, 1H, J=6.0Hz), 4.25 (ABq, 2H, J=43.8, 15.3 Hz), 4.57-4.79 (m, 1H), 6.36 (d, 1H,J=9.6 Hz), 7.46-7.48 (m, 2H), 7.53 (s, 1H), 7.57-7.63 (m, 3H), 7.85 (t,1H, J=6.3 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.65 (d, 1H, J=5.4 Hz). ¹³C NMR(D₂O) δ 20.33, 20.45, 36.87, 47.77, 48.22, 59.04, 114.10, 119.38,125.90, 126.99, 130.69, 137.16, 139.46, 139.85, 140.66, 148.01, 150.87,151.39. ES-MS m/z 457 [M+H]+. Anal. Calcd. forC₂₆H₂₈N₆O₂−.3.0HBr.3.4H₂O.0.2C₄H₁₀O: C, 41.52; H, 5.17; N, 10.84; Br,30.92. Found: C, 41.70; H, 4.90; N, 10.71; Br, 30.63.

Example 142

COMPOUND 142:N-3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-benzamide(hydrobromide salt) Preparation ofN-{3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-benzamide

To a solution ofN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine(166 mg, 0.50 mmol) in DMF (3 mL) was added 1-hydroxybenzotriazolehydrate (100 mg, 0.74 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (142 mg,0.74 mmol), and benzoic acid (73 mg, 0.59 mmol). The reaction mixturewas stirred overnight at room temperature. Then it was diluted withethyl acetate (40 mL) and water (25 mL). The organic layer was washedwith saturated NaHCO₃ (30 mL) and brine (30 mL), dried (Na₂SO₄),filtered, concentrated, and dried in vacuo to afford a yellow oil.Purification by radial chromatography on silica gel (1 mm plate; usingNH₄OH/CH ³OH/CH₂Cl₂; 1:1:100→1:3:100) afforded the product as a yellowfoam (80 mg, 37%). ¹H NMR (CDCl₃) δ 1.68-1.74 (m, 4H), 2.02-2.04 (m,1H), 2.22 (m, 1H), 2.62-2.69 (m, 2H), 2.81 (t, 1H, J=4.8 Hz), 2.84-2.90(m, 2H), 3.34-3.38 (m, 1H), 3.55-3.59 (m, 1H), 4.01-4.05 (m, 2H),7.10-7.18 (m, 4H), 7.32 (t, 2H, J=7.8 Hz), 7.42-7.48 (m, 2H), 7.59 (dd,2H, J=8.0, 1.5 Hz), 7.65 (br s, 1H), 8.43 (dd, 1H, J=3.9, 1.2 Hz).

Preparation ofN-{3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(hydrobromidesalt)

To a solution of the amine (80 mg, 0.18 mmol) in acetic acid (2 mL) wasadded hydrobromide saturated acetic acid (2 mL). The reaction mixturewas stirred for 30 minutes. Then it was triturated with diethyl etherfour times to afford the title compound as a yellow solid (99 mg), whichwas dried in vacuo. ¹H NMR (D₂O) δ 1.73-1.86 (m, 2H), 1.93-2.01 (m, 1H),2.13-2.17 (m, 1H), 2.34-2.38 (m, 1H), 2.43-2.53 (m, 1H), 2.80-2.87 (m,1H), 2.95-2.97 (br m, 2H), 3.17-3.23 (m, 1H), 3.28-3.35 (m, 1H), 3.53(q, 1H, J=6.9 Hz), 4.28-4.54 (m, 3H),7.31-7.38 (m, 4H), 7.49-7.51 (m,3H), 7.63-7.72 (m, 3H), 8.24 (d, 1H, J=7.8 Hz), 8.55 (d, 1H, J=5.7 Hz).¹³C NMR (D₂O) δ 20.36, 20.49, 27.63, 28.08, 37.37, 48.27, 49.01, 60.18,114.12, 125.86, 126.98, 129.20, 130.75, 132.67, 132.99, 139.30, 140.59,147.99, 151.17, 172.84. ES-MS m/z 440 [M+H]⁺. Anal. Calcd. forC₂₇H₂₉N₅O.2.1HBr.2.2H₂O: C, 49.96; H, 5.51; N, 10.79; Br, 25.85. Found:C, 49.96; H, 5.45; N, 10.65; Br, 25.95.

Example 143

COMPOUND 143:N-{3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-5-bromo-nicotinamidePreparation ofN-[3-[([H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propel}-5-bromo-nicotinamide

To a solution of 5-bromonicotinic acid (120 mg, 0.60 mmol) in DMF (3 mL)was added 1-hydroxybenzotriazole hydrate (96 mg, 0.72 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (137 mg,0.72 mmol), N,N-diisopropylethylamine (0.21 mL, 1.19 mmol), andN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine(200 mg, 0.60 mmol). The reaction mixture was stirred at roomtemperature overnight. Then it was diluted with ethyl acetate (40 mL)and water (25 mL). The aqueous layer was concentrated and dried in vacuoto afford a brown oil. Purification by radial chromatography (1 mmplate, using NH₄OH/CH₃OH/CH₂Cl₂; 1:1:100→1:4:100) afforded the productas pale yellow foam (220 mg, 71%). ¹H NMR (CDCl₃) δ 1.59-1.85 (m, 4H),1.99-2.03 (m, 1H), 2.16-2.20 (m, 1H), 2.58-2.62 (m, 1H), 2.73-2.85 (m,3H), 3.27-3.34 (m, 1H), 3.50-3.54 (m, 1H), 3.95 (d, 2H, J=2.4 Hz),4.03-4.08 (m, 1H), 7.09-7.16 (m, 3H), 7.31 (br s, 1H), 7.42 (d, 1H,J=7.5 Hz), 7.58 (br s, 1H), 7.91 (t, 1H, J=5.7 Hz), 8.07 (t, 1H, J=2.1Hz), 8.40 (d, 1H, J=3.6 Hz), 8.64 (d, 1H, J=2.4 Hz), 8.74 (d, 1H, J=1.8Hz).

Preparation ofN-{3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-5-bromo-nicotinamide

To a solution of the above amine (220 mg, 0.42 mmol) in acetic acid (2mL) was added hydrobromide saturated acetic acid (2 mL). The reactionmixture was stirred for 30 minutes. Then it was triturated with diethylether four times to precipitate out the product. The solid wasre-dissolved in anhydrous methanol (0.5 mL) and was triturated twicewith diethyl ether. The pale yellow solid (225 mg) was dried in vacuo.¹H NMR (D₂O) δ 1.82-1.99 (m, 4H), 2.17-2.21 (m, 1H), 2.38-2.42 (m, 1H),2.50-2.59 (m, 1H), 2.86-2.95 (m, 1H), 3.00-3.02 (m, 2H), 3.19-3.25 (m,1H), 3.36-3.43 (m, 1H), 4.32 (ABq, 2H, J=45.2, 16.2 Hz), 4.57 (dd, 1H,J=10.7, 5.4 Hz), 7.43-7.46 (m, 2H), 7.59-7.62 (m, 2H), 7.83 (dd, 1H,J=7.5, 6.0 Hz), 8.08 (t, 1H, J=1.8 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.51 (d,1H, J=1.5 Hz), 8.65 (d, 1H, J=5.1 Hz), 8.74 (d, 1H, J=1.8 Hz). ¹³C NMR(D₂O) δ 20.47, 27.48, 27.68, 37.82, 48.12, 48.88, 59.78, 114.04, 121.93,125.94, 126.96, 130.59, 132.11, 139.48, 140.66, 142.49, 142.93, 148.09,149.65, 149.81, 151.20. ES-MS m/z 521 [M+H]⁺. Anal. Calcd. forC₂₆H₂₇N₆OBr.2.9HBr.2.1H₂O: C, 39.52; H, 4.32; N, 10.64; Br, 39.44.Found: C, 39.47; H, 4.33; N, 10.26; Br, 39.55.

Example 144

COMPOUND 144: Cinnoline-4-carboxylicacid-{3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-amide(hydrobromide salt) Preparation of cinnoline-4-carboxylic acid-{3-[(1H-benzoimidazol-2-ylmethyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-amide

To a solution of cinnoline-4-carboxylic acid (80 mg, 0.46 mmol) in DMF(3 mL) was added 1-hydroxybenzotriazole hydrate (74 mg, 0.55 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg,0.55 mmol), N,N-diisopropylethylamine (0.16 mL, 0.92 mmol), andN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine(154 mg, 0.46 mmol). The reaction mixture was stirred for 3 days. Thenit was diluted with ethyl acetate (40 mL) and water (25 mL) and thephases were separated. The organic layer was washed with saturatedNaHCO₃ (30 mL) and saturated NaCl (30 mL). The combined aqueous layerwas washed with ethyl acetate (2×30 mL). The combined organic layer wasdried (MgSO₄), filtered, concentrated, and dried in vacuo to afford ayellow oil. Purification by radial chromatography on silica gel (1 mmplate; using NH₄OH/CH₃OH/CH₂Cl⁻²; 1:1:100→1:2:100) afforded the productas a yellow foam (85 mg, 38%). ¹H NMR (CDCl₃) δ 1.61-1.67 (m, 1H),1.80-1.90 (m, 3H), 2.00-2.06 (m, 1H), 2.20-2.24 (m, 2H), 2.64-2.75 (m,3H), 3.00-3.06 (m, 1H), 3.27-3.29 (m, 1H), 3.80-3.83 (m, 1H), 3.86 (d,2H, J=3.6 Hz), 4.02 (dd, 1H, J=10.1, 6.0 Hz), 6.78 (dd, 1H, J=7.5 Hz),7.12-7.17 (m, 2H), 7.21 (d, 1H, J=6.9 Hz), 7.59 (br s, 1H), 7.67-7.73(m, 2H), 7.78-7.83 (m, 1H), 8.06 (d, 1H, J=8.4 Hz), 8.14 (br s, 1H),8.48 (d, 1H, J=8.4 Hz), 9.11 (s, 1H.

Preparation of cinnoline-4-carboxylicacid-{3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-amide(hydrobromide salt)

To a solution of the above amine (85 mg, 0.17 mmol) in acetic acid (2mL) was added hydrobromide saturated acetic acid (2 mL) and the reactionmixture was stirred for 30 minutes. Then it was triturated with diethylether three times and the precipitate was dried in vacuo. Then the solidwas re-dissolved in methanol (0.5 mL) and it was triturated with diethylether an additional three times. The yellow solid (61 mg) was dried invacuo. ¹H NMR (D₂O) δ 1.65-1.89 (m, 3H), 2.04 (q, 1H, J=12.9 Hz),2.18-2.23 (m, 1H), 2.41-2.44 (m, 1H), 2.59-2.68 (m, 1H), 2.89-3.01 (m,3H), 3.32-3.57 (m, 2H), 4.38 (ABq, 2H, J=48.3, 15.9 Hz), 4.58-4.61 (m,1H), 7.32-7.37 (m, 2H), 7.49-7.57 (m, 2H), 7.82 (t, 1H, J=6.6 Hz),7.89-8.08 (m, 3H), 8.33 (d, 1H, J=7.8 Hz), 8.46 (d, 1H, J=8.4 Hz), 8.65(d, 1H, J=5.7 Hz), 8.92 (s, 1H). ES-MS m/z 492 [M+H]⁺. Anal. Calcd. forC₂₉H₂₉N₇O.2.8HBr.2.0H₂O: C, 46.19; H, 4.78; N, 13.00; Br, 29.67. Found:C, 46.35; H, 4.92; N, 12.68; Br, 29.50.

Example 145

COMPOUND 145: Preparation ofN-{4-[1H-benzolimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-6-hydroxynicotinamidehydrobromide

To a solution of 6-hydroxynicotinic acid (0.049 g, 0.35 mmoles) in DMF(2.7 mL) was added EDC (0.083 g, 0.43 mmoles), HOBT (0.056 g, 0.41mmoles) andN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(0.1 g, 0.29 mmoles) and the reaction stirred overnight at roomtemperature. Ethyl acetate (40 mL) and water (25 mL) were added and theorganic layer was washed with brine (30 mL) and saturated aqueous NaHCO₃(30 mL). The aqueous layers were extracted with ethyl acetate (3×30 mL)and the combined organic extracts dried with Na₂SO₄ and concentrated.The crude product was purified by radial chromatography on silica gel (1mm plate, 2% MeOH/1% NH₄OH/CH₂Cl₂, then 10% MeOH/1% NH₄OH/CH₂Cl₂) togiveN-{4-[1H-benzolimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-6-hydroxynicotinamideas an offwhite foam (30 mg, 16%).

Using General Procedure D, the free base was converted to the HBr saltto form COMPOUND 145 (42 mg. 81%). ¹H NMR (D₂O): δ 1.1-1.24 (m, 2H),1.27-1.4 (m, 2H), 1.75-1.85 (m, 1H), 1.85-2.01 (m, 1H), 2.04-2.15 (m,1H), 2.15-2.31 (m, 1H), 2.50-2.53 (m, 1H), 2.71-2.8 (m, 1H), 2.80-3.05(m, 2H), 3.09-3.2 (m, 1H), 3.22-3.30 (m, 1H), 4.31-4.60 (m, 3H),6.48-6.51 (d, 1H, J=9.3 Hz), 7.45-7.47 (m, 2H), 7.61-7.62 (m, 4H),7.82-7.86 (t, 1H, J=7.2 Hz,), 8.3-8.33 (d, 1H, J=7.8 Hz), 8.60-8.62 (d,1H, J=5.4 Hz). ¹³C NMR (D₂O): δ 20.44, 20.65, 25.93, 26.48, 27.68,39.05, 49.88, 52.68, 62.22, 114.01, 115.18, 119.26, 125.89, 126.76,130.65, 137.11, 139.27, 140.41, 140.53, 148.05, 151.29, 152.59, 165.27,166.17. ES-MS m/z 471.4 (M+H). Anal. Calcd for C₂₇H₃₀N₆O₂.3.1 HBr.1.8H₂O.0.8 C₄H₁₀O: C, 44.61; H, 5.54; N, 10.34; Br, 30.46. Found: C, 44.42;H, 5.30; N, 10.26; Br, 30.77.

Example 146

COMPOUND 146: Preparation ofN-{4-[(1H-benzolimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-benzamidehydrobromide

To a solution of benzoic acid in DMF (3 mL) was added EDC (0.097 g, 0.51mmol), HOBT (0.064 g, 0.47 mmol),N¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(0.12 g, 0.34 mmol) and DIPEA. The orange solution was stirred at roomtemperature overnight then diluted with dichloromethane (20 mL) andwater (20 mL). The organic layer was washed with brine (20 mL) andsaturated NaHCO₃ solution (20 mL), dried with Na₂SO₄ and concentrated togive an orange oil. The crude product was purified by radialchromatography on silica gel (1 mm plate, 2% MeOH/1% NH₄OH/CH₂Cl₂, then4% MeOH/1% NH₄OH/CH₂Cl₂) to giveN-{4-[(1H-benzolimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-benzamideas an offwhite foam (80 mg, 51%).

Using general procedure D, conversion of the foam to the HBr salt andits reprecipitation in methanol/ether formed COMPOUND 146 (93 mg. 77%).H NMR (D₂O): δ 1.25-1.37 (m, 2 H), 1.37-1.54 (m, 2H), 1.75-1.85 (m, 1H),1.90-2.02 (m, 1H), 2.02-2.23 (m, 1H), 2.25-2.35 (m, 1H), 2.50-2.60 (m,1H), 2.70-2.82 (m, 1H), 2.82-3.0 (m, 2H), 3.13-3.26 (m, 2H), 4.33-4.57(m, 3H), 7.44 (s, 4H), 7.49-7.50 (m, 2H), 7.50-7.60 (m, 1H), 7.60-7.75(m, 2H), 7.75-7.80 (m, 1H), 8.21 (d, 1H, J=7.8 Hz), 8.54 (d, 1H, J=5.1Hz). ¹³C NMR (D₂O): 20.44 (2 carbons), 25.83, 26.48, 27.61, 39.29,49.50, 52.22, 61.57, 114.08 (2 carbons), 125.85, 126.87 (2 carbons),127.15 (2 carbons), 129.21 (2 carbons), 130.73, 132.57, 132.59, 139.13,140.26 (2 carbons), 147.97, 151.32, 152.10. ES-MS m/z 454.4 (M+H). Anal.Calcd. for C₂₈H₃₁N₅O.2.2 HBr.1.9H₂O.0.3C₄H₁₀O: C, 50.97; H, 5.86; N,10.18; Br 25.55. Found: C, 51.23; H, 5.70; N, 10.17; Br, 25.28.

Example 147

COMPOUND 147: Preparation of pyridine-2-carboxylic acid{4-[1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-amidehydrobromide

To a solution of picolinic acid (0.042 g, 0.34 mmol) in DMF (2.5 mL) wasadded EDC (0.077 g, 0.40 mmol), HOBT (0.051 g, 0.38 mmol),N¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(0.096 g, 0.28 mmol) and DIPEA (0.10 ml, 0.56 mmol) and the orangesolution stirred at room temperature overnight. The mixture was dilutedwith dichloromethane (20 mL) and water (20 mL) and the organic layerwashed with brine (3×20 mL) and saturated aqueous NaHCO₃ solution (20mL). The organic layer was dried with Na₂SO₄ and concentrated to anorange oil. The crude product was purified by radial chromatography onsilica gel (1 mm plate, 2% MeOH/1% NH₄OH/CH₂Cl₂ and then 4% MeOH/1%NH₄OH/CH₂Cl₂) to give pyridine-2-carboxylic acid{4-[1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-amideas a offwhite foam (55 mg, 44%)

Using General Procedure D, the free base was converted to thehydrobromide with HBr/acetic acid to yield COMPOUND 147 (67.4 mg. 73%)as an offwhite solid. ¹H NMR (D₂O): δ 1.25-1.40 (m, 2H), 1.40-1.68 (m,2H), 1.75-1.95 (m, 1H), 2.00-2.12 (q, 1H, J=13.2 Hz), 2.12-2.25 (m, 1H),2.26-2.48 (m, 1H), 2.51-2.57 (m, 1H), 2.75-2.88 (m, 1H), 2.90-3.05 (m,2H), 3.25-3.48 (m, 2H), 4.44-4.58 (q, 2H, J=17.1 Hz), 4.48-4.55 (m, 1H),7.44-7.47 (m, 2H), 7.61-7.64 (m, 2H), 7.77-7.98 (m, 3H), 8.23-8.30 (m,2H), 8.58-8.73 (m, 2H), ¹³C NMR (D₂O): δ 20.43, 20.54, 25.92, 26.43,27.65, 39.61, 49.47, 52.34, 61.77, 114.05 (2 carbons), 123.99, 125.87,126.79 (2 carbons), 129.10, 130.69, 139.24, 140.49 (2 carbons), 144.32,145.18, 145.69, 148.02, 151.33, 152.38, 162.96. ES-MS m/z 455.4 (M+H).Anal. Calcd. for C₂₇H₃₀N₆O.3.2 HBr.2.1H₂O.0.2 C₄H₁₀O: C, 43.58; H, 5.18;N, 10.97; Br, 33.37. Found: C, 43.44; H, 5.05; N, 10.91; Br, 33.64.

Example 148

COMPOUND 148: Preparation ofN-{4-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,78-tetrahydroquinolin-8-yl)-amino]-butyl}-5-bromo-nicotinamidehydrobromide

To a solution of 5-Bromonicotinic acid (0.061 g, 0.30 mmol) in DMF (2.2mL) was added EDC (0.086 g, 0.45 mmol), HOBT (0.57 g, 0.42 mmol),COMPOUND 18 free base (0.1 05 g, 0.30 mmol) and DIPEA (0.10 ml, 0.57mmol) and the orange solution stirred at room temperature overnight. Themixture was diluted with dichloromethane (20 mL) and water (20 mL) andthe organic layer washed with brine (20 mL) and aqueous saturated NaHCO₃solution (20 mL). The organic layer was dried with Na₂SO₄ andconcentrated to an orange oil. The crude product was purified by radialchromatography on silica gel (1 mm plate, 2% MeOH/1% NH₄OH/CH₂Cl₂) togive the final product as an offwhite foam (110 mg, 69%).

Using General Procedure D, the foam was converted to the hydrobromidesalt by dissolving it in acetic acid/HBr and precipitating the HBr saltin methanol/ether to yield COMPOUND 148 (133 mg. 78%) as an offwhitesolid. ¹H NMR (D₂O): δ 1.23-1.37 (m, 4H), 1.37-1.5 (m, 4H), 1.75-1.90(m, 2H), 1.90 (q, 2H, J=11.7 Hz), 2.12-2.25 (m, 2H), 2.26-2.45 (m, 2H),2.48-2.55 (m, 2H), 2.75-2.88 (m, 2H), 2.90-3.01 (m, 4H), 3.12-3.25 (m,2H), 3.23-3.37 (m, 2H), 4.33 (d, 1H, J=17.1 Hz) 4.51-4.60 (m, 1H), 4.60(d, 1H, J=17.1 Hz), 7.4-7.42 (m, 2H), 7.58-7.61 (m, 2H), 7.76-7.93 (m,1H), 8.09 (s, 1H) 8.30 (d, 1H, J=7.5 Hz), 8.50 (s, 1H), 8.60 (d, 1H,J=5.4 Hz), 8.82 (d, 1H, J=3 Hz). ¹³C NMR (D₂O): δ 20.45, 20.63, 26.01,26.56, 27.69, 39.55, 49.66, 52.53, 62.02, 113.96 (2 carbons), 121.79,125.90, 126.74 (2 carbons), 130.62 (2 carbons), 132.32, 138.30, 140.54,141.84, 143.51, 148.06, 150.30, 151.28, 152.49, 165.0. ES-MS m/z 534.8(M+H). Anal. Calcd for C₂₇H₂₉N₆BrO.3.1 HBr.2.1H₂O.0.1 C₄H₁₀O: C, 39.67;H, 4.52; N, 10.13; Br, 39.49. Found: C, 39.63; H, 4.40; N, 10.09; Br,39.45.

Example 149

COMPOUND 149: Preparation of quinoline-2-carboxylic acid{2-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-amidehydrobromide

To a solution of isoquinolinecarboxylic acid (0.061 g, 0.55 mmol) andN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(0.12, 0.35 mmoles) in DMF (2.5 mL) was added EDC (0.10 g, 0.52 mmol),HOBT (0.066 g, 0.49 mmol) and DIPEA (0.12 ml, 0.69 mmol) and the orangesolution stirred at room temperature for 2 days. The mixture was dilutedwith dichloromethane (20 mL) and water (20 mL) and the organic layerwashed with brine (3×20mL) and saturated NaHCO₃ solution (20 mL). Theorganic layer was dried with Na₂SO₄ and concentrated to an orange oil.The crude product was purified by radial chromatography on silica gel (1mm plate, 2% MeOH/1% NH₄OH/CH₂Cl₂) to give final product as an offwhitefoam (95 mg, 53%)

Using General Procedure D: the freebase was converted to thehydrobromide salt by dissolving the foam in acetic acid and addingacetic acid saturated with hydrobromic acid. The HBr salt wasprecipitated out of methanol/ether to yield COMPOUND 149 (115 mg. 72%)as an offwhite solid. ¹H NMR (D₂O): δ 1.37-1.65 (m, 4H), 1.75-1.95 (m,1H), 2.12-2.25 (m, 1H), 2.27-2.48 (m, 1H), 2.57-2.75 (m, 1H), 2.75-3.02(m, 2H), 3.28-3.51 (m 2H), 4.35 (d, 2H, J=17.1Hz), 4.56 (d, 2H, J=16.8Hz), 4.5-4.65 (m, 1H), 7.18-7.21 (dd, 2H, J=6.3, 3.0 Hz), 7.40-8.25-8.29(m, 2H), 8.41 (d, 1H, J=7.8 Hz), 8.68 (d, 1H, J=5.4 Hz). ¹³C NMR (D₂O):δ 20.45, 20.69. 26.35, 26.78, 27.67, 39.93, 49.42, 52.52, 61.85, 113.78(2 carbons), 124.56, 125.89, 126.41 (2 carbons), 126.94, 127.08, 128.56,130.51 (2 carbons), 131.70, 133.75, 135.99, 139.29, 139.67, 140.56 (2carbons), 148.07, 148.96, 151.24, 152.29. ES-MS m/z 505.4 (M+H). Anal.Calcd. for C₃₁H₃₂N₆O.3.1 HBr.1.9 H₂O.0.8 C₄H₁₀O: C, 48.38; H, 5.57; N,9.90; Br, 29.18. Found: C, 48.47; H, 5.52; N, 9.93; Br, 29.04.

Example 150

COMPOUND 150: Preparation of cinnoline-4-carboxylic acid{4-[(1H-benzoimidazol-2-ylmethyl)-5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-amide

To a solution of cinnoline-4-carboxylic acid (0.061 g, 0.34 mmol) andN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine(0.12, 0.34 mmoles) in DMF (2.5 mL) was added EDC (0.10 g, 0.52 mmol),HOBT (0.065 g, 0.48 mmol), and DIPEA (0.12 ml, 0.69 mmol) and the orangesolution stirred at room temperature overnight. The mixture was dilutedwith dichloromethane (20 mL) and water (20 mL) and the organic layerwashed with brine (3×20 mL) and saturated NaHCO₃ solution (20 mL). Theorganic layer was dried with Na₂SO₄ and concentrated to an orange oil.The crude product was purified by radial chromatography on silica gel (1mm plate, 2% MeOH/1% NH₄OH/CH₂Cl₂) to give final product as an offwhitefoam (656 mg, 37%).

Using General procedure D: the foam was converted to its HBr salt inHBr/AcOH and COMPOUND 150 (79.3 mg. 76%) was precipitated as an offwhitesolid. ¹H NMR (D₂O): δ 1.25-1.62 (m, 8H), 1.74-1.97 (m, 2H), 1.97-2.25(m, 4H), 2.25-2.50(m, 2H), 2.50-2.75 (m, 2H), 2.75-3.13 (m, 6H)3.23-3.55 (m, 4H), 7.0-7.13 (m, 2H), 7.27-7.37 (m, 2H), 7.76-7.87 (m,1H), 7.95 (s, 2H), 7.99-8.07 (m, 1H), 8.31 (d, 1H, J=7.5 Hz), 8.48 (d,1H, J=9.0 Hz), 8.61 (d, 1H, J=5.1 Hz), 9.00 (s, 1H). 1³C NMR (D₂O): δ20.47, 20.69, 26.25, 26.85, 27.68, 39.42, 49.64, 52.69, 62.04, 113.62 (2carbons), 123.94, 124.21, 125.89, 126.28 (2 carbons), 128.95, 130.45 (2carbons), 130.79, 133.55, 134.73, 139.28, 140.60 (2 carbons), 141.07,148.08, 150.42, 151.29, 152.44, 166.11. ES-MS m/z 506.4 (M+H) Anal.Calcd. for C₃₀H₃₁N₇.3.1HBr.2.3 H₂O.0.2 C₄H₁₀O: C, 45.52; H, 5.05; N,12.06; Br, 30.48. Found: C, 45.59; H, 4.91; N, 12.03; Br, 30.31.

Example 152

COMPOUND 152: Preparation ofN-{2-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-ethyl}-3,5-dichloro-isonicotinamide

To a stirred solution of (2,3-dihydroxy-propyl)-carbamic acid tert-butylester (0.955 g, 5.00 mmol) in water (12 mL) was added sodium periodate(2.35 g, 11.0 mmol). The mixture was stirred at room temperature for I hand then extracted with dichloromethane (3×10 mL). The extracts weredried over Na₂SO₄ and concentrated to give (2-oxo-ethyl)-carbamic acidtert-butyl ester as a colorless liquid (778 mg, 98%). ¹H NMR (CDCl₃) δ1.45 (s, 9 H), 4.07 (d, J=4.5 Hz, 2 H), 5.20 (brs, 1H), 9.65 (s, 1 H).

To a solution of2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylicacid tert-butyl ester (0.378 g, 1.00 mmol) and (2-oxo-ethyl)-carbamicacid tert-butyl ester (0.159 g, 1.00 mmol) in dichloromethane (5 mL) wasadded sodium triacetoxyborohydride(0.223 g, 1.05 mmol). The mixture wasstirred at room temperature for 15 h and then poured into saturatedaqueous NaHCO₃ (30 mL). The mixture was extracted with chloroform (3×20mL). The extracts were dried over Na₂SO₄ and concentrated. Purificationof the crude material by column chromatography on silica gel (98:1:1CH₂Cl₂—CH₃OH—NH₄OH) provided 499 mg (96%) of2-{[(2-tert-butoxycarbonylamino-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester as a yellow foam. ¹H NMR (CDCl₃) δ 1.48 (s, 9 H),1.64 (s, 9 H), 1.69-1.85 (m, 2 H), 1.94-1.99 (m, 1 H), 2.24 (m,1 H),2.61-2.87 (m, 3 H), 3.09-3.19 (m, 3 H), 4.07 (dd, J=9.9 Hz, 5.7 Hz, 1H), 4.26 (d, J=16.2 Hz, 1 H), 4.52 (d, J=16.2 Hz, 1 H), 6.98 (dd, 1H,J=7.7 Hz, 4.7 Hz, 1 H), 7.26-7.32 (m, 3 H), 7.57 (brs, 1 H), 7.74 (m, 1H), 7.86 (m, 1 H), 8.41 (d, J=3.9 Hz, 1 H).

To a solution of2-{[(2-tert-butoxycarbonylamino-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (0.490 g, 0.94 mmol) in dichloromethane (4 mL) wasadded trifluoroacetic acid (4 mL). The mixture was stirred at roomtemperature for 1 h. Sodium hydroxide (2 M, 30 mL) was added and themixture was extracted with chloroform (3×20 mL). The extracts were driedover Na₂SO₄ and concentrated. Purification of the crude material bycolumn chromatography on silica gel (90:5:5 CH₂Cl₂—CH₃OH—NH₄OH) provided294 mg (97%) ofN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamineas a colorless oil. ¹H NMR (CDCl₃) δ 1.60-1.75 (m, 1 H), 1.87-1.98 (m, 1H), 2.01 (m, 1 H), 2.22 (m,1 H), 2.56-2.85 (m, 6 H), 4.03 (m, 1 H), 4.04(d, J=16.8 Hz, 1 H), 4.17 (d, J=16.8 Hz, 1 H), 7.11-7.21 (m, 3 H), 7.40(d, J=7.8 Hz, 1 H), 7.56 (brs, 2 H), 8.55(d, J=4.2 Hz, 1 H).

To a suspension of 3,5-dichloro-isonicotinoyl chloride (0.34 mmol) inTHF (3 mL) at 0° C. was added a solution ofN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine(0.100 g, 0.312 mmol) in dichloromethane (3 mL), THF (1 mL) and Et₃N(0.087 mL). After stirring at 0° C. for 5 min., the mixture was warmedto room temperature and stirred for 2.5 h. The solvents were evaporatedand the residue was taken into saturated aqueous NaHCO₃ (30 mL). Themixture was extracted with chloroform (3×20 mL). The extracts were driedover Na₂SO₄ and concentrated. Purification of the crude material bycolumn chromatography on silica gel (200:1:1 CH₂Cl₂—CH₃OH—NH₄OH)provided 55 mg (44%) of COMPOUND 152 as a pale yellow solid ¹H NMR(CDCl₃) δ 1.55-1.70 (m, 1H), 1.78-1.85 (m, 1 H), 2.03 (m, 1 H), 2.29(m,1 H), 2.66-2.82 (m, 3 H), 3.20 (d, J=13.5 Hz, 1 H), 3.39 (m, 1 H),3.55 (m, 1 H), 3.90(dd, J=10.8 Hz, 5.7 Hz, 1 H), 4.12 (d, J=16.7 Hz,1H), 4.30 (d, J=16.7 Hz, 1 H), 6.99 (dd, 1H, J=7.8 Hz, 4.8 Hz, 1 H),7.15-7.21 (m, 2 H), 7.27 (m, 1 H), 7.41 (d, J=7.8 Hz, 1 H), 7.54 (d,J=4.2 Hz, 1 H), 7.63 (d, J=4.2 Hz, 1 H), 8.40 (m, 1 H), 8.56 (s, 2 H);¹³C NMR (CDCl₃) δ 21.79, 23.08, 29.32, 38.68, 48.54, 49.25, 61.63,119.35, 122.24, 122.69, 123.19, 129.64, 133.76, 135.76, 138.70, 143.50,144.39, 146.46, 148.03, 154.85, 157.38, 162.22; ES-MS m/z 496 (M+H).Anal. Calcd. for C₂₅H₂₄N₆Cl₂O.0.9CH₂Cl₂: C, 54.40; H, 4.55; N, 14.70;Cl, 23.56. Found: C, 54.64; H, 4.53; N, 14.62 Cl, 23.41.

Example 153

COMPOUND 153: Preparation ofN-{3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-3,5-dichloro-isonicotinamide

To a solution of (3-hydroxy-propyl)-carbamic acid tert-butyl ester (200mg, 1.15 mmol) in CH₂Cl₂ (11.5 mL) cooled to 0° C. was added Dess-Martinperiodinane (489 mg, 1.15 mmol) and the resulting mixture was stirred atroom temperature for 1 hour. The mixture was diluted with CH₂Cl₂ (40 mL)and washed with 1 N NaOH (2×10 mL). The organic phase was dried (MgSO₄),filtered and concentrated under reduced pressure. The colourless syrup(180 mg) was used in the next reaction without further purification.

To a stirred solution of2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylicacid tert-butyl ester (390 mg, 0.98 mmol), (3-oxo-propyl)-carbamic acidtert-butyl ester (170 mg, 0.98 mmol) from above and THF (9.8 mL) wasadded NaBH(OAc)₃ (623 mg, 2.94 mmol) and the resulting mixture wasstirred at room temperature for 1 hour. AcOH (56 μL, 0.98 mmol) wasadded and the mixture stirred at room temperature overnight. The mixturewas concentrated under reduced pressure, diluted with CH₂Cl₂ (40 mL) andwashed with 1N NaOH (10 mL). The aqueous was extracted with (2×20 mL)and the combined organic extracts were dried (MgSO₄), filtered andconcentrated under reduced pressure. A solution of the resulting orangefoam in CH₂Cl₂ (4 mL) and TFA (4 mL) was stirred at room temperature for2.5 hours. The mixture was concentrated under reduced pressure,partially dissolved in H₂O (2 mL), basified with 1N NaOH and extractedwith CH₂Cl₂ (3×25 mL). The combined organic extracts were dried (MgSO₄),filtered and concentrated under reduced pressure. Purification by columnchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 100:7:1) affordedN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine(290 mg, 75% over 3 steps) as a white foam.

To a mixture of 3,5-dichloro-isonicotinic acid (52 mg, 0.27 mmol) inCH₂Cl₂ (1.1 mL) cooled to 0° C. was added oxalyl chloride (70 μL, 0.81mmoL) and DMF (1 drop) and the resulting mixture was stirred at 0° C.for 5 minutes and at room temperature for 1.5 hours. The mixture wasconcentrated under reduced pressure and dried in vacuo for 5 minutes. Tothe resulting beige solid in THF (3 mL) was addedN¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diaminefrom above (100 mg, 0.30 mmol) and Et₃N (76 μL, 0.54 mmol) and theresulting mixture was stirred at room temperature for 3 hours. Themixture was concentrated under reduced pressure, diluted with EtOAc (40mL) and washed consecutively with saturated aqueous NaHCO₃ (5 mL) andsaturated aqueous NaCl (5 mL). The organic phase was dried (MgSO₄),filtered, and concentrated under reduced pressure. Purification bycolumn chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 100:1:1)afforded COMPOUND 153 (55 mg, 40%) as a white foam. ¹H NMR (CDCl₃) δ1.70-1.94 (m, 4 H), 2.04-2.15 (m, 1H), 2.26-2.33 (m, 1H), 2.64-2.96 (m,4H), 3.10-3.15 (m, 1H), 3.68 (d, 1H, J=15.6 Hz), 3.80 (d, 1H, J=15.6Hz), 3.98-4.07 (m, 1H), 4.19-4.25 (m, 1H), 6.83 (dd, 1H, J=7.8, 4.8 Hz),7.20-7.23 (m, 2H), 7.35-7.40 (m, 2H), 7.66-7.68 (m, 2H), 8.34 (s, 2H),8.78 (br s, 1H); ¹³C NMR (CDCl₃) δ 21.69, 21.92, 26.70, 29.38,39.04,49.41, 49.87, 59.45, 111.10, 119.37, 122.63, 122.95, 129.27,135.68, 138.29, 143.68, 146.10, 147.70, 154.94, 157.51. 162.27. ES-MSm/z 510 (M+H). Anal. Calcd. for C₂₆H₂₆N₆Cl₂O.0.3CH₂Cl₂.0.1H₂O: C, 58.86;H, 5.03; N, 15.66; Cl, 17.17. Found: C, 59.22; H, 5.21; N, 15.74; Cl,16.80.

Example 154

COMPOUND 154: Preparation ofN-{4-[(1-allyl-1H-benzimidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydro-quinolin-8-ylamino]-butyl}-3,5-dichloro-isonicotinamide

4-[(1-Allyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butylhydrochloride salt (120 mg, 0.215 mmol) was neutralized with 1M NaOH (25mL) and the free base was extracted with CHCl₃ (25 mL×3). The combinedorganic solution was dried (Na₂SO₄), filtered and concentrated underreduced pressure, giving the free base as a cloudy, yellow oil.

To a suspension of 3,5-dichloropyridine-4-carboxylic acid (82 mg, 0.43mmol) and DMF (1 drop) in CH₂Cl₂ (4 mL) was added oxalyl chloride (0.11mL, 1.3 mmol). The resulting white suspension was stirred at roomtemperature under nitrogen for 35 minutes, and then the solvent wasevaporated under reduced pressure. The crude acid chloride was driedunder reduced pressure, and then a solution of the free base in THF (4mL) and NEt₃ (0.05 mL, 0.4 mmol) were added. The resulting suspensionwas stirred at room temperature under nitrogen for 1 hour and 10minutes. The mixture was diluted with CH₂Cl₂ (25 mL) and washed with H₂O(10 mL). The aqueous solution was extracted with CH₂Cl₂ (10 mL) and theorganic solution was washed with saturated aqueous NaHCO₃ (20 mL). Theaqueous solution was again extracted with CH₂Cl₂ (10 mL) and thecombined organic solution was dried (Na₂SO₄), filtered and concentratedunder reduced pressure. Purification by flash column chromatography onsilica (CH₂Cl₂/MeOH/NH₄OH, 19:1:0.2) gave the amide as a white foam(92.3 mg, 0.164 mmol, 76%). ¹H NMR (CDCl₃) δ 1.40-1.60 (m, 2H),1.63-1.89 (m, 3H), 1.95-2.19 (m, 3H), 2.60-3.03 (m, 5H), 3.55-3.67 (m,1H), 3.70 (d, 1H, J=13.2 Hz), 3.86 (d, 1H, J=13.2 Hz), 4.26 (dd, 1H,J=8.1, 6.3 Hz), 4.61 (d, 1H, J=17.1 Hz), 4.67 (dd, 1H, J=16.4, 5.1 Hz),4.96 (d, 1H, J=10.5 Hz), 5.57-5.71 (m, 1H), 6.85 (dd, 1H, J=7.5, 4.8Hz), 7.17-7.25 (m, 4H), 7.61-7.65 (m, 1H), 7.89 (d, 1H, J=3.6 Hz), 8.32(s, 2H), 8.97 (br. t, 1H). 13C NMR (CDCl₃) δ 23.1, 23.8, 24.0, 28.2,30.9, 40.3, 47.2, 49.8, 51.3, 61.0, 111.6, 118.1, 120.5, 123.5, 123.7,124.4, 130.6, 134.1, 136.6, 137.1, 138.7, 143.7, 145.1, 147.6, 149.0,153.7, 158.7, 164.2. ES-MS m/z 564 (M+H). Anal. Calcd. forC₃₀H₃₂Cl₂N₆O.0.2C₄H₁₀O.0.1CH₂Cl₂: C, 63.24; H, 5.87; N, 14.32; Cl,13.29. Found: C, 63.02; H, 5.74; N, 14.31; Cl, 13.04.

Example 155

COMPOUND 155: Preparation ofN-{4-[(1H-benzimidazol-2-ylmethyl)-(R)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-35-dichloro-isonicotinamide

To a suspension of 3,5-dichloropyridine-4-carboxylic acid (135 mg, 0.70mmol) and DMF (2 drops) in CH₂Cl₂ (7 mL) was added oxalyl chloride (0.18mL, 2.1 mmol). The resulting suspension was stirred at room temperatureunder nitrogen for 35 minutes and then the solvent was evaporated underreduced pressure. The crude acid chloride was dried under reducedpressure, and then a solution ofN¹-(1H-Benzimidazol-2-ylmethyl)-N¹-(R)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine(120 mg, 0.344 mmol) in THF (4 mL) and NEt₃ (0.06 mL, 0.4 mmol) wereadded. The resulting suspension was stirred at room temperature undernitrogen for 1 hour. The reaction was diluted with saturated aqueousNaHCO₃ (25 mL) and was extracted with CH₂Cl₂ (25 mL×3). The combinedorganic solution was dried (MgSO₄), filtered and concentrated underreduced pressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH/NH₄OH, 32:1:0.2) gave the amide as a white foam (134 mg,0.256 mmol, 74%). ¹H NMR (CDCl₃) δ 1.47-1.61 (m, 4H), 1.63-1.78 (m, 1H),1.81-195 (m, 1H), 3.87 (d, (m, 1H), 2.15-2.25 (m, 1H), 2.60-2.85 (m,4H), 3.10-3.23 (m, 1H), 3.31-3.43 (m, 1H), 3.87 (d, 1H, J=16.2 Hz), 3.98(d, 1H, J=16.2 Hz), 4.05 (dd, 1H, J=9.6, 5.7 Hz), 6.94 (br. t, 1H), 7.12(dd, 1H, J=7.8, 4.8 Hz), 7.15-7.20 (m, 2H), 7.42 (d, 1H, J=7.8 Hz),7.44-7.62 (m, 2H), 8.39 (s, 2H), 8.47 (d, 1H, J=4.8 Hz). ¹³C NMR (CDCl₃)δ 21.6, 23.9, 25.8, 26.9, 29.4, 39.6, 49.6, 50.5, 62.1, 122.1, 122.7,129.2, 135.1, 138.0, 143.2, 146.8, 147.7, 156.4, 157.7, 162.6. ES-MS m/z523 (M+H), 525 (M+2+H). Anal. Calcd. for C₂₇H₂₈Cl₂N₆O.0.3H₂O.0.2CH₂Cl₂:C, 59.85; H, 5.35; N, 15.40; Cl, 15.59. Found: C, 59.62; H, 5.38; N,15.22; Cl, 15.98.

Example 156

COMPOUND 156: Preparation ofN-{4-[(1-allyl-1H-imidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydro-quinolin-8-ylamino]-butyl}-35-dichloro-isonicotinamide

N¹-(1-Allyl-1H-imidazol-2-ylmethyl)-N¹-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine,Hydrochloride salt (115.1 mg, 0.216 mmol) was neutralized with 1M NaOH(25 mL) and the free base was extracted with CHCl₃ (25 mL×3). Thecombined organic solution was dried (Na₂SO₄), filtered and concentratedunder reduced pressure, giving the free base as a cloudy, yellow oil.

To a suspension of 3,5-dichloropyridine-4-carboxylic acid (83 mg, 0.43mmol) and DMF (1 drop) in CH₂Cl₂ (4 mL) was added oxalyl chloride (0.11mL, 1.3 mmol). The resulting white suspension was stirred at roomtemperature under nitrogen for 30 minutes, and then the solvent wasevaporated under reduced pressure. The crude acid chloride was driedunder reduced pressure, and then a solution of the free base in THF (4mL), and NEt₃ (0.04 mL, 0.3 mmol) were added. The resulting suspensionwas stirred at room temperature under nitrogen for 1 hour. The reactionwas taken up into saturated aqueous NaHCO₃ (25 mL) and extracted withCH₂Cl₂ (25 mL×3). The combined organic solution was dried (Na₂SO₄),filtered and concentrated under reduced pressure. Purification by flashcolumn chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1) gave theamide as an off-white foam (77.4 mg, 0.151 mmol, 70%). ¹H NMR (CDCl₃) δ1.38-1.57 (m, 2H), 1.60-2.16 (m, 7H), 2.61-2.86 (m, 5H), 3.37 (d, 1H,J=13.5 Hz), 3.57 (d, 1H, J=13.5 Hz), 3.63-3.72 (m, 1H), 4.20 (dd, 1H,J=8.4, 6.3 Hz), 4.35 (dd, 1H, J=13.7, 5.1 Hz), 4.52 (dd, 1H, J=13.7, 5.7Hz), 4.71 (dd, 1H, J=17.1, 0.9 Hz), 5.02 (dd, 1H, J=10.2, 0.9 Hz),5.56-5.69 (m, 1H), 6.74 (d, 1H, J=1.2 Hz), 6.81 (d, 1H, J=1.2 Hz), 6.86(dd, 1H, J=7.5, 4.8 Hz), 7.30 (d, 1H, J=6.9 Hz), 7.74 (d, 1H, J=3.9 Hz),8.34 (s, 2H), 9.44 (br. s, 1H). ¹³C NMR (CDCl₃) δ 21.8, 22.1, 22.3,27.3, 29.7, 38.5, 47.1, 48.1, 49.3, 59.5, 117.4, 120.5, 122.2, 127.5,129.4, 133.5, 135.3, 137.5, 145.7, 146.1, 147.6, 157.6, 162.9. ES-MS m/z513 (M+H). Anal. Calcd. for C₂₆H₃₀Cl₂N₆O.0.2H₂O.0.05CH₂Cl₂: C, 60.02; H,5.90; N, 16.12; Cl, 14.28. Found: C, 60.20; H, 5.90; N, 15.80; Cl,14.28.

Example 157

COMPOUND 157: Preparation of(Cis-2-Aminomethyl-cylcopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-amine(hydrochloride salt) Preparation oftert-Butyl-(Cis-2-chloromethyl-cyclopropylmethyoxy)-dimethyl-silane

To a stirred 0° C. solution of dimethylcis-1,2-cyclopropanedicarboxylate (22.0 g, 140 mmol) in anhydrous THF(185 mL) was added 1 M lithium aluminum hydride solution in THF (180 mL,180 mmol) over 20 min under a nitrogen atmosphere. The cooling bath wasremoved and stirring was continued for 1.5 h. The mixture was carefullyquenched with deionized water (7 mL), followed by 15% NaOH solution (7mL), followed by deionized water (20 mL). The resultant precipitate wasremoved by filtration, the filter cake was washed with ethyl acetate (50mL), and the filtrate was concentrated. The resultant orange oil waspurified by column chromatography on silica gel (50:1 CH₂Cl₂/MeOH) toafford the diol (10.2 g, 72%) as a pale yellow oil.

To a stirred 0° C. suspension of sodium hydride (3.8 g, 95 mmol) inanhydrous THF (130 mL) under a nitrogen atmosphere was added a solutionof the diol from above (9.22 g, 90 mmol) in anhydrous THF (50 mL) andstirring was continued for 10 min. To the above stirred solution wasadded tert-butyldimethylsilyl chloride (14.3 g, 95 mmol) in three parts,over 1 min. The cooling bath was removed, and stirring was continued for30 min. The mixture was poured into saturated sodium bicarbonatesolution (200 mL) and extracted with dichloromethane (3×150 mL). Theorganic extracts were combined, dried over Na₂SO₄, and concentrated. Theresultant yellow oil (22 g) was purified by column chromatography onsilica gel (5:1 hexanes/EtOAc) to provide the desired mono-protecteddiol (18.9 g, 97%) as a pale yellow oil.

To a stirred solution of the alcohol (18.9 g, 87 mmol) from above andtriethylamine (36 mL, 260 mmol) in dichloromethane (300 mL) was addedneat methanesulfonyl chloride (15 mL, 190 mmol) over 5 min. The stirredmixture was heated to reflux for 16 h; then it was cooled to roomtemperature, washed with water (2×200 mL), washed with brine (200 mL),dried over MgSO₄, and concentrated. Purification of the resultant brownoil (21 g) by column chromatography on silica gel (20:1 hexanes/EtOAc)afforded the title compound (13.5 g, 66%) as a yellow oil. ¹H NMR(CDCl₃) δ 0.06 (s, 3H), 0.07 (s, 3H), 0.38 (q, 1H, J=6.0 Hz), 0.85-0.89(m, 1H), 0.90 (s, 9H), 1.23-1.36 (m, 2H), 3.57-3.68 (m, 3H), 3.78-3.84(m, 1H).

Preparation of Methanesulfonic acidCis-2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-cyclopropylmethylester

A stirred slurry oftert-butyl-(cis-2-chloromethyl-cyclopropylmethyoxy)-dimethyl-silane(13.5 g, 57 mmol) from above and potassium phthalimide (16.0 g, 86 mmol)in DMF (380 mL) was heated to 100° C. under a nitrogen atmosphere for 3h. the mixture was cooled to room temperature and concentrated. Theresultant residue was dissolved in ethyl acetate (500 mL), washed withbrine (3×200 mL), dried over MgSO₄, and concentrated. Purification ofthe crude material by column chromatography on silica gel (9:1hexanes/EtOAc) gave the desired phthalimide (8.55 g, 43%) as a whitecrystalline solid.

The phthalimide (8.5 g, 25 mmol) from above was stirred vigorously in amixture THF (100 mL) and 1 N HCl (100 mL) for 20 min. The mixture wasconcentrated to remove THF then extracted with dichloromethane (3×100mL). The combined organic extracts were dried over MgSO₄ andconcentrated. The resultant material was filtered through a plug ofsilica gel. First the plug was eluted with 9:1 hexanes/EtOAc to washaway the non-polar impurities; then it was eluted with EtOAc to providethe desired alcohol (5.6 g, 97%) as a white solid.

To a stirred 0° C. solution of the alcohol (5.6 g, 24 mmol) from aboveand triethylamine (5.0 mL, 36 mmol) in dichloromethane (80 mL) was addedmethanesulfonyl chloride (2.3 mL, 29 mmol) and stirring was continuedfor 40 minutes at room temperature. The reaction was quenched byaddition of saturated sodium bicarbonate solution (100 mL). The layerswere separated and the aqueous layer was extracted with dichloromethane(50 mL). The organic layers were combined, dried over MgSO₄, andconcentrated to give the title compound (7.9 g, 100%) as a white solid.¹H NMR (CDCl₃) δ 0.53 (q, 1H, J=6.0 Hz), 0.91-0.99 (m, 1H), 1.28-1.41(m, 1H), 1.55-1.62 (m, 1H), 3.01 (s, 3H), 3.67-3.83 (m, 2H), 4.24 (dd,1H, J=12.0, 9.0 Hz), 4.58 (dd, 1H, J=10.5, 7.5 Hz), 7.72-7.76 (m, 2H),7.83-7.87 (m, 2H).

Preparation of(Cis-2-Aminomethyl-cylcopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-amine(hydrochloride salt) (COMPOUND 157)

A stirred slurry of methanesulfonic acid(1R,2S)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-cyclopropylmethylester (7.4 g, 24 mmol) from above,(1H-benzimidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-amine(7.6 g, 20 mmol, prepared according to the procedures in Bridger et al.U.S. patent application Ser. No. 09/535,314), diisopropylamine (5.2 mL,30 mmol), and potassium iodide (170 mg, 1.0 mmol) in anhydrousacetonitrile (200 mL) was heated to 60° C. for 16 h. The mixture wascooled to room temperature and concentrated. The resultant residue waspartitioned between ethyl acetate (200 mL) and saturated sodiumbicarbonate solution (100 mL). The layers were separated and the organiclayer was washed with water (2×100 mL) and brine (2×100 mL), dried overMgSO₄ and concentrated. Purification of the resultant crude brown oil byrepetitive column chromatography on silica gel (first column: 2%MeOH/CH₂Cl₂, second column: 5% NH₄OH/EtOAc) provided the desiredprotected amine (2.3 g, 19%) as a white foamy solid.

To a stirred solution of the protected amine (6.3 g, 11 mmol) from abovein ethanol (50 mL) was added hydrazine hydrate (3.1 mL, 64 mmol). Themixture was heated to 50° C. for 1 h with stirring. The resultant whiteslurry was cooled to room temperature, diluted with diethyl ether (50mL), filtered through a glass-fritted funnel to remove the precipitate,and concentrated. Purification of the crude material by repetitivecolumn chromatography on silica gel (first column: 20: 1:1CH₂Cl₂/MeOH/NH₄OH, second column: 50:1:1 CH₂Cl₂/MeOH/NH₄OH) afforded thedesired primary amine (2.80 g, 74%) as a white foamy solid.

Following General Procedure D: Conversion of the free base (2.80 g, 7.7mmol) from above to the hydrochloride salt provided COMPOUND 157 (3.30g, 87%) as a white solid. 1H NMR (D₂O) δ 0.08 (q, 1H, J=5.0 Hz), 0.22(q, 1H, J=5.0 Hz), 0.46-0.52 (m, 1H), 0.62 (q, 1H, J=6.0 Hz), 1.01-1.09(m, 2H), 1.80-1.92 (m, 1H), 2.02-2.10 (m, 1H), 2.16-2.21 (m, 1H),2.32-2.38 (m, 1H), 2.51-2.63 (m, 1H), 2.64-2.71 (m, 1H), 2.99-3.16 (m,4H), 4.43-4.69 (m, 3H), 7.55-7.59 (m, 2H), 7.75-7.85 (m, 3H), 8.32 (t,1H, J=7.5Hz), 8.62 (dd, 1H, J=7.5, 6.2 Hz); ¹³C NMR (D₂O) δ 9.99, 10.85,12.41, 13.59, 15.40, 20.46, 20.69, 27.65, 39.84, 48.54, 49.49, 51.76,61.21, 61.81, 114.31, 114.35, 125.80, 126.56, 126.61, 131.41, 131.69,139.41, 139.53, 140.33, 140.46, 147.74, 147.86, 151.31, 151.97, 152.61;ES-MS m/z 362 (M+H). Anal. Calcd. for C₂₂H₂₇N₅.3.0HCl.1.3H₂O: C, 53.46;H, 6.65; N, 14.17; Cl, 21.52. Found: C, 53.67; H, 6.87; N, 13.85; Cl,21.53.

The enantiomeric purity of COMPOUND 157 at the5,6,7,8-tetrahydroquinolin-8-yl center) was determined to be 100% ee bychiral HPLC using the following conditions: Instrument: Hewlett Packard1100 HPLC (VWD2); Column: ChiralPak AD-H, 0.46 cm×25 cm; Mobile Phases:A: 90:10 hexanes/reagent alcohol with 0.1% DEA, B: reagent alcohol;Isocratic: 90% A, 10% B; Total Run Time: 40 min; Flow Rate: 0.5 mL/min;Temperature: 40° C.; Detector: UV@270 nm; Injection volume: 10 μL.

Retention time of the R enantiomer=17.0 min.

Retention time of the S enantiomer=20.4 min.

Example 158

COMPOUND 158: Preparation ofN-(2-{[(1H-benzimidazol-2-ylmethyl)-(S)-(5,6,7.8-tetrahydro-quinolin-8-yl)-amino]-methyl}-cis-cyclopropylmethyl)-3,5-dichloro-isonicotinamide

((1R,2S)-2-Aminomethyl-cylcopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-amine,hydrochloride salt (107.2 mg, 0.217 mmol) was neutralized with 1M NaOH(25 mL) and the free base was extracted with CHCl₃ (25 mL×3). Thecombined organic solution was dried (Na₂SO₄), filtered and concentratedunder reduced pressure, giving the free base as a white foam.

To a suspension of 3,5-dichloropyridine-4-carboxylic acid (85 mg, 0.44mmol) and DMF (1 drop) in CH₂Cl₂ (4 mL) was added oxalyl chloride (0.11mL, 1.3 mmol). The resulting white suspension was stirred at roomtemperature under nitrogen for 30 minutes, and then the solvent wasevaporated under reduced pressure. The crude acid chloride was driedunder reduced pressure, then NEt₃ (0.06 mL, 0.4 mmol) and a solution ofthe free base in THF (4 mL) were added. The solution was stirred at roomtemperature under nitrogen for 1 hour and 15 minutes. The reaction wastaken up into CH₂Cl₂ (25 mL) and washed with H₂O (10 mL). The aqueoussolution was extracted with CH₂Cl₂ (10 mL×2) and the combined organicsolution was washed with saturated aqueous NaHCO₃ (15 mL). This aqueoussolution was extracted with CH₂Cl₂ (10 mL) and the combined organicsolution was dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH, 99:1, increased to 49:1) gave diastereomer A as a whitefoam (44.9 mg, 0.084 mmol, 39%) along with diastereomer B as a whitefoam (48.0 mg, 0.090 mmol, 41%).

Characterization data for diastereomer A: ¹H NMR (CDCl₃) δ 0.07 (q, 1H,J=5.2 Hz), 0.72-0.84 (m, 1H), 1.09-1.35 (m, 2H), 1.61-1.96 (m, 2H),2.03-2.18 (m, 2H), 2.24-2.40 (m, 2H),2.77-2.88 (m,2H), 3.32 (dd, 1H,J=13.2, 5.1 Hz),4.41 (ddd, 1H, J=13.8, 9.6, 3.0 Hz), 4.68 (dd, 1H,J=10.5, 5.4 Hz), 6.81 (dd, 1H, J=7.8, 4.8 Hz),7.16-7.28 (m, 2H),7.33-7.45 (m, 2H), 7.64 (d, 1H, J=6.6 Hz), 8.36 (s, 2H), 9.48 (d, 1H,J=8.1 Hz), 10.37 (br. s, 1H). ¹³C NMR (CDCl₃) δ 9.5, 12.4, 16.2, 20.9,21.4, 28.9, 38.5, 49.1, 51.9, 58.9, 110.5, 119.1, 121.7, 122.3, 122.7,129.0, 133.4, 135.2, 137.8, 142.9, 143.4, 145.4, 147.2, 154.1, 157.3,162.3. ES-MS m/z 535 (M+H), 537 (M+2+H). Anal. Calcd. forC₂₈H₂₈Cl₂N₆O.0.5CH₃OH.0.4CH₂Cl₂: C, 59.29; H, 5.30; N, 14.35; Cl, 16.96.Found: C, 59.46; H, 5.24; N, 14.31; Cl, 16.60.

Characterization data for diastereomer B:¹H NMR(CDCl₃) δ-0.01 (dd, 1H,J=9.0, 6.0 Hz), 0.54-0.92 (m, 3H), 1.65-1.92 (m, 2H), 2.03-2.15 (m, 1H),2.18-2.30 (m, 1H), 2.47 (dd, 1H, J=13.5, 10.8 Hz), 2.67 (ddd, 1H,J=14.6, 10.7, 2.1 Hz), 2.74-2.86 (m, 2H), 3.29 (dd, 1H, J=13.5, 3.3 Hz),3.77 (d, 1H, J=15.9 Hz), 3.92 (d, 1H, J=15.9 Hz), 4.08 (dd, 1H, J=9.6,5.4 Hz), 4.41 (ddd, 1H, J=14.6, 8.4, 4.8 Hz), 6.97 (dd, 1H, J=7.8, 4.8Hz), 7.20 (d, 2H, J=5.7 Hz), 7.39 (d, 1H, J=7.2 Hz), 7.59 (br. s, 1H),7.70 (d, 1H, J=3.9 Hz), 8.38 (s, 2H), 8.60 (d, 1H, J=7.5 Hz).

Example 159

COMPOUND 159: Preparation ofN-{(E)-2-aminomethyl-4-[(1H-benzimidazol-2-ylmethyl)-(S)-(5,6,7,8-tetrahydro-guinolin-8-yl)-amino]-but-2-enyl}-3,5-dichloro-isonicotinamideandN-{(Z)-2-aminomethyl-4-[(1H-benzimidazol-2-ylmethyl)-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-but-2-enyl}-35-dichloro-isonicotinamide

3-Aminomethyl-N-(1H-benzoimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-but-2-ene-1,4-diamine,hydrochloride salt (213.8 mg, 0.365 mmol) was neutralized with 1M NaOH(25 mL) and the free base was extracted with CHCl₃ (25 mL×3). Thecombined organic solution was dried (Na₂SO₄), filtered and concentratedunder reduced pressure, giving the free base as a yellow foam.

To a suspension of 3,5-dichloropyridine-4-carboxylic acid (86 mg, 0.45mmol) and DMF (1 drop) in CH₂Cl₂ (4 mL) was added oxalyl chloride (0.12mL, 1.4 mmol). The resulting white suspension was stirred at roomtemperature under nitrogen for 30 minutes, and then the solvent wasevaporated under reduced pressure. The crude acid chloride was driedunder reduced pressure, and then a solution of the free base in THF (7mL), and NEt₃ (0.08 mL, 0.6 mmol) were added. The resulting suspensionwas stirred at room temperature under nitrogen for 1.5 hours. Thereaction was taken up into H₂O (25 mL) and extracted with CH₂Cl₂ (25mL×3). The combined organic solution was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1) gave bothregioisomeric amides as an approximately 1:1 mixture (26.1 mg, 0.047mmol, 13%) (the regioisomeric ratio was estimated based ondifferentiation of the two components in the ¹H NMR spectrum. Separationof the two isomers was not observed during chromatography or duringanalysis by HPLC.) along with the bis-amide as a yellow foam (39.9 mg,0.055 mmol, 15%).

Data for the mono-amide mixture: ¹H NMR (CDCl₃) δ 1.67-1.96 (m, 6H),2.02-2.30 (m, 4H), 2.71-2.95 (m, 4H), 3.24 (s, 2H), 3.27-3.39 (m, SH),3.44-3.51 (m, 1H, J=15.3 Hz), 3.76 (d, 1H, J=15.3 Hz), 3.83-3.98 (m,5H), 4.08-4.22 (m, 3H), 5.47 (t, 1H, J=6.9 Hz), 5.55 (t, 1H, J=6.9 Hz),6.52 (br. s, 1H), 6.97-7.08 (m, 3H), 7.12-7.23 (m, 3H), 7.36-7.49 (m,6H), 8.06 (d, 1H, J=4.2 Hz), 8.47 (s, 2H), 8.51 (s, 2H), 8.56 (d, 1H,J=3.9 Hz), 9.79 (br. t, 1H). ES-MS m/z 551 (M+H). Anal. Calcd. forC₂₈H₂₉Cl₂N₇O.2.0H₂O.0.2CH₂Cl₂.0.4C₄H₈O₂: C, 56.04; H, 5.78; N, 15.35;Cl, 13.32. Found: C, 56.19; H, 5.38; N, 15.36; Cl, 13.02.

Example 160

COMPOUND 160:3-Aminomethyl-N¹-(1H-benzoimidazol-2-ylmethyl)-N¹-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl)-but-2-ene-1,4-diaminehydrochloride salt Preparation of(3-tert-Butoxycarbonylamino-2-hydroxy-propyl)-carbamic acid tert-butylester

To a solution of 1,3 diamino-2-hydroxypropane (10 g, 0.11 mol) inmethanol (500 ml) was added di-tert-butyl dicarbonate (48 g, 0,22 mol)and the reaction stirred for 2 hours at room temperature under a N₂atmosphere. The mixture was concentrated to afford the product as alight yellow oil (31.9 g, 100%). ¹HNMR (CD₃OD) δ 1.44 (s, 18H), 3.10 (m,4H), 3.63 (m, 1H).

Preparation of (3-tert-Butoxycarbonylamino-2-oxo-propyl)-carbamic acidtert-butyl ester

To a solution of dimethyl sulfoxide (25.2 ml, 0.36 mol) in methylenechloride (357 ml) at −78° C. (dry ice/acetone) was added a solution ofoxalyl chloride (20 ml, 0.23 mol) in methylene chloride (115 ml). Thereaction mixture was stirred at −78° C. for 30 min under an atmosphereof N₂ then a solution of(3-tert-Butoxycarbonylamino-2-hydroxy-propyl)-carbamic acid tert-butylester (31.9 g, 0.11 mol) in methylene chloride (300 ml) andtriethylamine (75 ml, 0.54 mol) were added. The reaction was stirred for16 hours, allowing the reaction to warm up to room temperature. Themixture was diluted with water (800 ml) and extracted with methylenechloride (2×300 ml). The combined organic extracts were dried (Na₂SO₄),filtered, and concentrated in vacuo to afford a yellowish oil.Purification via column chromatography on silica gel (ethylacetate:hexane, 3:7, v/v) afforded the product as a white solid (28 g,88%). ¹H NMR (CDCl₃) δ 1.44 (s, 18H), 4.04 (m, 4H), 5.19 (s, 1H).

Preparation of4-tert-butoxycarbonylamino-3-(tert-butoxycarbonylamino-methyl)-but-2-enoicacid ethyl ester

To a solution of (3-tert-Butoxycarbonylamino-2-oxo-propyl)-carbamic acidtert-butyl ester (28 g, 97.0 mmol) dissolved in benzene (350 ml) wasadded (carbethoxymethylene)-triphenyl phosphorane (89 g, 0.26 mol) andthe reaction mixture stirred for 16 hours at 45° C., under a N₂atmosphere. The mixture was concentrated and purified by columnchromatography on silica gel (ethyl acetate:hexane, 1:3, v/v) to affordthe product as a yellowish solid (26 g, 75%). ¹H NMR (CDCl₃) δ 1.43 (s,18H), 1.59 (s, 3H), 3.90 (d, 2H, J=4.75 Hz), 4.11 (m, 4H), 5.35 (m, 2H),5.87 (s, 1H).

Preparation of[2-(tert-butoxycarbonylamino-methyl)-4-hydroxy-but-2-enyl]-carbamic acidtert-butyl ester

To a solution of4-tert-butoxycarbonylamino-3-(tert-butoxycarbonylamino-methyl)-but-2-enoicacid ethyl ester (7.0 g, 19.5 mmol) in tetrahydrofuran (195 ml), at areaction temperature of −78° C. (dry ice/acetone) was added a solutionof diissobutylaluminum hydride (1 M in CH₂Cl₂, 59 ml, 59 mmol) and thereaction mixture stirred at −78° C. for 2 hours under a N₂ atmosphere.The reaction was quenched with a saturated solution of sodium tartratetetrahydrate (300 ml), stirred vigorously until the layers clarifiedthen extracted with methylene chloride (2×100 ml). The combined organicextracts were dried (Na₂SO₄), filtered, and concentrated in vacuo toafford a yellow oil. Purification via column chromatography on silicagel (ethyl acetate:hexane, 1:1, v/v) afforded the product as a yellowoil (5.90 g, 96%). ¹HNMR (CDCl₃) δ 1.43 (s, 18H), 3.72 (s, 4H), 4.18 (t,2H), 4.76 (s, 1H), 5.54 (s, 1H), 5.96 (t, 1H).

Preparation of methane sulfonic acid 4-tert-butoxycarbonylamino-3-(tert-butoxycarbonyl amino-methyl)-but-2-enyl ester

To a solution of[2-(tert-butoxycarbonylamino-methyl)-4-hydroxy-but-2-enyl]-carbamic acidtert-butyl ester (9.13 g, 29 mmol) in dichloromethane (290 ml), at areaction temperature of 0° C. was added triethylamine (8.1 ml, 58 mmol)and methanesulfonyl chloride (2.24 ml, 29 mmol). The reaction mixturewas stirred at 0° C. for 30 min under a N₂ atmosphere then diluted witha saturated solution of ammonium chloride (250 ml). The aqueous layerwas extracted with methylene chloride (3×150 ml). The combined organicextracts were dried (Na₂SO₄), filtered, and concentrated in vacuo toafford a yellow oil (11.0 g, 93%). ¹HNMR (CDCl₃) δ 1.43 (s, 18H), 3.03(s, 3H), 3.78 (m, 4H), 4.92 (d, 1H, J=4.75 Hz), 5.01 (s, 1H), 5.17 (s,1H), 5.66 (t, 1H).

Preparation of2-{[[4-tert-butoxycarbonylamino-3-(tert-butoxycarbonylamino-methyl)-but-2-enyl]-N—(S)-(5,6,7,8-tetrahydro-quinolin-8yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester

To a solution methane sulfonic acid 4-tert-butoxycarbonylamino-3-(tert-butoxycarbonyl amino-methyl)-but-2-enyl ester (5.2 g, 13.2mmol) in acetonitrile (60 ml) was added potassium iodide (1.1 g, 6.6mmol), diisopropylethylamine (2.3 ml, 13.2 mmol), and a solution of2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (5.0 g,13.2 mmol) in acetonitrile (60 ml) and the reaction stirred at roomtemperature for 2 hours under a N₂ atmosphere. A solution of methanesulfonic acid 4-tert-butoxycarbonyl amino-3-(tert-butoxycarbonylamino-methyl)-but-2-enyl ester (5.2 g, 13.2 mmol) in acetonitrile (60ml) was added and the reaction mixture stirred at room temperature for16 hours under a N₂ atmosphere. The reaction mixture was concentrated,redissolved in methylene chloride (200 ml), and diluted with saturatedNaCl (200 ml). The aqueous layer was extracted with methylene chloride(3×150 ml) and the combined organic extracts were dried (Na₂SO₄),filtered, and concentrated in vacuo to afford a yellow oil (6.3 g, 70%).¹HNMR (CDCl₃) δ 1.43 (s, 18H), 2.10 (m, 3H), 2.53 (m, 1H), 2.77 (m, 1H),3.19 (m, 1H), (m, 1H), 3.52 (m, 3H), 3.77 (m, 1H), 3.94 (m, 1H), 4.29(m, 3H), 5.21 (s, 1H), 5.47 (s, 1H), 6.73 (s, 1H), 7.05 (s, 1H), 7.25(s, 1H), 7.69 (m, 3H), 8.25 (s, 1H).

Preparation of3-Aminomethyl-N-(1H-benzoimidazol-2-ylmethyl)-N—(S)-(5,6,7,8-tetrahydro-quinolin-8-yl)-but-2-ene-1,4-diamine

A solution of2-{[[4-tert-butoxycarbonylamino-3-(tert-butoxycarbonylamino-methyl)-but-2-enyl]-N—(S)-(5,6,7,8-tetrahydro-quinolin-8yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester dissolved in HCl saturated acetic acid (35 ml) wasstirred for 5 hours at room temperature under a N₂ atmoshpere. Thesolution was added dropwise to diethyl ether (550 ml) to yield a chunkywhite precipitate. The white solid was isolated via suction filtrationunder a steady stream of nitrogen, washed with diethyl ether and driedat 40° C. in vacuo overnight (3.8 g, 71%). ¹HNMR (D₂O) δ 1.79 (m, 1H),1.83 (m, 1H), 2.01 (m, 1H), 2.43 (m, 1H), 3.00 (s, 2H), 3.31 (m, 2H),3.76 (m, 5H), 4.49 (m, 3H), 6.66 (dd, 1H, J=8.77, 3.95 Hz), 7.62 (m,2H), 7.88 (m, 3H), 8.41 (d, 1H, J=7.45 Hz), 8.83 (d, 1H, J=5.7 Hz); ¹³CNMR δ (D₂O) 20.32, 27.61, 37.09, 42.34, 46.68, 48.93, 59.29, 114.32,126.01, 126.98, 128.73, 131.22, 136.30, 139.63, 140.36, 148.08, 150.73.ES-MS m/z 377 (M +H). Anal. Calcd. ForC₂₂H₂₈N₆.93.93HCl.2.16H₂O.0.46(C₂H₄O₂): C, 46.96; H, 6.55; N, 14.44; Cl,23.74. Found: C, 46.97; H, 6.67; N, 14.31; Cl, 23.75.

Example 161

COMPOUND 161: Preparation of(1H-Benzoimidazol-2-ylmethyl)-(2-piperidin-3-ylidene-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

To a solution of 3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester(1.9169 g, 9.5 mmol) in CH₂Cl₂ (50 mL) was added Dess-Martin Periodinane(4.8470 g, 11.4 mmol), and the mixture was stirred at room temperaturefor 5 hours. CH₂Cl₂ (75 mL), saturated NaHCO₃ (100 mL), and 20% aqueoussodium thiosulfate (100 mL) were added, and the mixture was stirred for30 minutes. The layers were separated, and the aqueous layer wasextracted with CH₂Cl₂ (1×75 mL). The organic extracts were washed withbrine (1×100 mL), dried (Na₂SO₄), and concentrated. Purification of thecrude material by column chromatography on silica gel (4:1hexanes-EtOAc) provided 1.80 g (95%) of 3-oxo-piperidine-1-carboxylicacid tert-butyl ester as a colorless oil. ¹H NMR (CDCl₃) δ 1.49 (s, 9H),1.93-2.02 (m, 2H), 2.46 (t, 2H, J=6 Hz), 3.58 (t, 2H, J=6 Hz), 4.00 (s,2H).

To a solution of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester(1.80 g, 9.0 mmol) in benzene (20 mL) was added(carbethoxymethylene)-triphenylphosphorane (4.72 g, 13.6 mmol) andstirred at 65° C. for 3.5 hours. The reaction was brought to reflux (80°C.) and stirred for 23 hours before it as cooled to room temperature andconcentrated. Purification of the crude material by columnchromatography on silica gel (6:1 hexanes-EtOAc) provided 0.4874 g (20%)of cis-3-ethoxycarbonylmethylene-piperidine-1-carboxylic acid tert-butylester as white crystals. A NOESY experiment was run to determine whichproduct was the desired cis isomer. ¹H NMR (CDCl₃) δ 1.23-1.30 (m, 3H),1.45 (s, 9H), 1.70-1.76 (m, 2H), 2.34 (t, 2H, J=6 Hz), 3.48 (t, 2H, J=6Hz), 4.13-4.21 (m, 2H), 4.61 (s, 2H), 5.66 (s, 1H).

A solution of cis-3-ethoxycarbonylmethylene-piperidine-1-carboxylic acidtert-butyl ester (0.4701 g, 1.7 mmol) in CH₂Cl₂ (17 mL) was cooled to−78° C. and was flushed with argon. 1.0 M Diisobutylaluminum hydride inhexanes (5.1 mL, 5.1 mmol) was added dropwise to this solution, and thereaction was stirred at −78° C. for 50 minutes. The reaction was broughtto room temperature and stirred for 3.5 hours before it was cooled to 0°C. Saturated aqueous KNa Tartrate (Rochelle's salt, 6 mL) was addeddropwise, and then water (10 mL) and CH₂Cl₂ (75 mL) were added. Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(2×50 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated. Purification of the crude material by columnchromatography on silica gel (3:1 hexanes-EtOAc) provided 0.1652 g (43%)of cis-3-(2-hydroxy-ethylidene)-piperidine-1-carboxylic acid tert-butylester. ¹H NMR (CDCl₃) δ 1.45 (s, 9H), 1.60-1.68 (m, 2H), 2.27 (t, 2H,J=6.1 Hz), 2.87 (s, 1H), 3.47 (t, 2H, J=6 Hz), 3.96 (s, 2H), 4.06-4.13(m, 2H), 5.59 (s, 1H).

To a solution of cis-3-(2-hydroxy-ethylidene)-piperidine-1-carboxylicacid tert-butyl ester (0.1652 g, 0.7 mmol) in CH₂Cl₂ (10 mL) at −78° C.was slowly added triethylamine (0.2 mL, 1.4 mmol) and methane sulfonylchloride (0.1 mL, 0.9 mmol). The reaction was stirred at −78° C. for 40minutes and then stirred at room temperature for 40 minutes. Water (10mL) and CH₂Cl₂ (40 mL) were added and the layers were separated. Theaqueous phase was extracted with CH₂Cl₂ (3×50 mL), and the combinedorganic extracts were dried (Na₂SO₄) and concentrated to yield 0.1985 g(93%) of cis-3-(2-methanesulfonyloxy-ethylidene)-piperidine-1-carboxylicacid tert-butyl ester as a pale pink oil. ¹H NMR (CDCl₃) δ 1.46 (s, 9H),1.78 (s, 2H), 2.31 (t, 2H, J=6 Hz), 3.01 (s, 3H), 3.48 (t, 2H, J=6 Hz),4.01 (s, 2H), 4.82 (d, 2H, J=7.4 Hz), 5.46 (t, 1H, J=7.4 Hz).

To a solution ofcis-3-(2-methanesulfonyloxy-ethylidene)-piperidine-1-carboxylic acidtert-butyl ester (0.1985 g, 0.6 mmol) in CH₃CN (6 mL) was added2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylicacid tert-butyl ester (0.2531 g, 0.6 mmol), potassium iodide (0.0110 g,0.06 mmol), and DIPEA (0.2 mL, 0.9 mmol) and was stirred at 60° C. for17 hours. Saturated NaHCO₃ (15 mL) and CH₂Cl₂ (50 mL) were added andseparated. The aqueous phase was extracted with CH₂Cl₂ (2×30 mL), andthe combined organic extracts were dried (Na₂SO₄) and concentrated.Purification of the crude material by column chromatography on silicagel (70:1:1 CH₂Cl₂—CH₃OH—NH₄OH) followed by another column on silica gel(ether saturated with NH₄OH) provided 0.1282 g (36%) ofcis-2-{[[2-(1-tert-butoxycarbonyl-piperidin-3-ylidene)-ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester as a white solid. ¹H NMR (CDCl₃) δ 1.41-1.47 (m,1H), 1.68 (s, 9H), 1.73 (s, 9H), 1.85-1.96 (m, 5H), 2.17 (s, 2H),2.59-2.79 (m, 2H), 3.21-3.31 (m, 1H), 3.37-3.60 (m, 3H), 3.72 (s, 1H),3.94-4.01 (m, 1H), 421-4.29 (m, 1H), 4.38-4.62 (m, 2H), 5.21-5.30 (m,1H), 6.94-6.98 (m, 1H), 7.27-7.28 (m, 3H), 7.68-7.71 (m, 1H), 7.79-7.82(m, 1H), 8.39-8.40 (m, 1H).

Following the general procedure D,cis-2-{[[2-(1-tert-butoxycarbonyl-piperidin-3-ylidene)-ethyl]-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (0.1282 g, 0.2 mmol) was converted to thehydrobromide salt followed by reprecipitation of the intermediate solidfrom methanol/ether gave COMPOUND 161 (0.1168 g, 87%) as a white solid.¹H NMR (D₂O) 1.12-1.21 (m, 2H), 1.58-1.67 (m, 3H), 1.79-1.94 (m, 2H),1.98-2.24 (m, 2H), 2.33-2.43 (m, 1H), 2.97-3.04 (m, 2H), 3.07-3.24 (m,2H), 3.46-3.65 (m, 2H), 3.78-3.84 (m, 1H), 4.29-4.38 (m, 1H), 4.49-4.61(m, 3H), 5.44 (s, 1H), 7.61-7.62 (m, 2H), 7.77-7.80 (m, 2H), 7.86 (t,11H, J=6.9 Hz), 8.34 (d, 1H, J=7.5 Hz), 8.64 (d, 11H, J=4.8 Hz). ¹³C NMR(D₂O) δ 20.36, 20.63, 23.60, 27.63, 30.03, 31.84, 43.82, 44.67,48.82,61.29, 114.22, 125.97, 126.29, 127.06, 130.93, 132.83, 139.48, 140.66,148.09, 150.93, 151.83. ES-MS m/z 388 (M+H). Anal. Calcd. forC₂₄H₂₉N₅.3.0HBr.2.3H₂O: C, 42.92; H, 5.49; N, 10.43; Br, 35.69. Found:C, 43.20; H, 5.38; N, 10.03; Br, 35.92.

Example 162

COMPOUND 162: Preparation ofN-{4-[(1H-Benzimidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-acetamide(free base)

N′-(1H-benzimidazol-2-ylmethyl)-N′—(S)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine(500 mg, 1.43 mmol) was dissolved in ethyl acetate (10 mL) to give ayellow solution. The reaction mixture was stirred at reflux for 48hours. The resulting yellow/orange solution was concentrated underreduced pressure to afford an orange oil. Purification via columnchromatography on silica gel (CH₂Cl₂:MeOH:NH₄OH, 90:5:5, v/v/v) affordedthe product as a pale yellow foam (56 mg, 10%). ¹H NMR (CDCl₃) δ1.37-1.45 (m, 4H), 1.65-1.73 (m, 1H), 1.85 (s, 3H), 1.87-1.90 (m, 1H),2.04-2.10 (m, 1 H), 2.14-2.22 (m, 1H), 2.60-2.65 (m, 1H), 2.69-2.77 (m,2H), 2.77-2.83 (m, 1H), 3.02-3.06 (m, 2H), 3.97 (d, 1H, J=15.0 Hz), 4.02(m, 1H), 4.08 (d, 1H, J=15.0 Hz), 5.48 (br t, 1H), 7.16-7.22 (m, 3H),7.44 (d, 1H, J=6.0), 7.53 (br s, 2H), 8.58 (d, 1H, J=3.0 Hz). ¹³C NMR(CDCl₃) δ 21.61, 23.60, 24.24, 26.10, 27.26, 29.51, 39.47, 49.82, 50.69,62.46, 115.26, 122.08, 122.69, 135.10, 137.92, 146.92, 156.89, 157.84,170.47. ES-MS m/z 392 [M+H]⁺. Anal. Calcd. for C₂₃H₂₉N₅O.0.7H₂O: C,68.36, H, 7.58; N, 17.33. Found: C, 68.45; H, 7.47; N, 17.25.

Example 163

COMPOUND 163: Preparation of{4-[(1H-Benzimidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-urea(free base) Preparation of COMPOUND 163

In a flask purged with nitrogen,N′-(1H-benzimidazol-2-ylmethyl)-N′—(S)-5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine(208 mg, 0.60 mmol) was dissolved in iso-propanol (4 mL) to give ayellow solution. Trimethylsilyl isocyanate (113 AL, 0.83mmol) was addedvia syringe and the reaction mixture was stirred at room temperature for18 hours. The resulting yellow solution was concentrated under reducedpressure to afford a yellow oil. Purification via column chromatographyon silica gel (CH₂Cl₂:MeOH:NH₄OH, 90:5:5, v/v/v) afforded the product asa white solid (167 mg, 71%). ¹H NMR (CDCl₃) δ 1.37-1.45 (m, 4H),1.65-1.75 (m, 1H), 1.88-1.92 (m, 1H), 2.00-2.07 (m, 1H), 2.17-2.24 (m,2H), 2.51-2.59 (m, 1H), 2.66-2.77 (m, 2H), 2.80-2.83 (m, 1H), 2.96-3.00(m, 2H), 3.95 (d, 1H, J=15.0 Hz), 4.03 (m, 1H), 4.04 (d, 1H, J=15.0 Hz),4.47 (s, 2H), 5.20 (br t, 1H), 7.16-7.22 (m, 3H), 7.43 (d, 1H, J=7.5),7.53 (br s, 2H), 8.55 (d, 1H, J=3.0 Hz). ¹³C NMR (CDCl₃) δ 21.51, 24.18,25.88, 27.64, 29.50, 40.34, 49.67, 50.99, 62.64, 111.64, 119.13, 122.19,122.74, 135.23, 137.99, 146.95, 156.64, 157.78, 159.33. ES-MS m/z 393[M+H]⁺. Anal. Calcd. for C₂₂H₂₈N₆O.0.15CH₂Cl₂: C, 65.65, H, 7.04; N,20.74. Found: C, 65.56; H, 7.26; N, 20.90.

Example 164

COMPOUND 164: Preparation of pyrazine-2-carboxylic acid{3-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-amidePreparation of pyrazine-2-carboxylic acid (3-hydroxy-propyl)-amide

To a solution of 3-amino-1-propanol (1.20 mL, 15.7 mmol) in CH₂Cl₂ (80mL) was added 2-pyrazinecarboxylic acid (1.99 g, 16.0 mmol), DIPEA (5.6mL, 32.1 mmol), HOBT (2.61 g, 19.3 mmol) and EDC.HCl (3.70 g, 19.3mmol). The solution was stirred at room temperature under nitrogen for14.5 hours, then was diluted with brine (25 mL). The layers wereseparated and the aqueous solution was extracted with EtOAc (50 mL×3)and CHCl₃ (50 mL×3). The combined organic solution was dried (Na₂SO₄),filtered and concentrated under reduced pressure. Purification by flashcolumn chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1) gave theamide as a white solid (1.94 g, 10.7 mmol, 68%). 1H NMR (CDCl₃) δ 1.83(quint, 2H, J=5.9 Hz), 3.03 (br. s, 1H), 3.61-3.74 (m, 4H), 8.12 (br. s,1H), 8.53 (dd, 1H, J=2.4, 1.5 Hz), 8.75 (d, 1H, J=2.4 Hz), 9.40 (d, 1H,J=1.5 Hz).

Preparation of pyrazine-2-carboxylic acid (3-oxo-propyl)-amide

To a solution of the amide (184 mg, 1.02 mmol) in CH₂Cl₂ (5 mL) wasadded Dess-Martin periodinane (468 mg, 1.10 mmol) and the reaction wasstirred at room temperature for 20 minutes. The mixture was diluted with10% aqueous Na₂S₂O₃ (20 mL) and saturated aqueous NaHCO₃ (20 mL),stirred vigorously for 15 minutes and extracted with CH₂Cl₂ (25 mL×3).The combined organic solution was dried (MgSO₄), filtered andconcentrated under reduced pressure giving the crude aldehyde as anorange solid (143 mg, 0.80 mmol, 78%). ¹H NMR (CDCl₃) δ 2.85 (quint, 2H,J=6.0 Hz), 3.77 (q, 2H, J=6.0 Hz), 8.16 (br. s, 1H), 8.50 (dd, 1H,J=2.4, 1.5 Hz), 8.72 (d, 1H, J=2.4 Hz), 9.35 (d, 1H, J=1.5 Hz), 9.83 (s,1H).

Preparation of COMPOUND 164

A solution of the aldehyde (140 mg, 0.78 mmol) and(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(201 mg, 0.72 mmol) in CH₂Cl₂ (4.5 mL) was stirred at room temperaturefor 10 minutes, then NaBH(OAc)₃ (180 mg, 0.85 mmol) was added. Thereaction mixture was stirred for another 6.5 hours, then was washed with1M NaOH (10 mL×2) and brine (10 mL). The organic solution was dried(MgSO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1)gave the tertiary amine as a yellow foam (271 mg, 0.63 mmol, 85%). ¹HNMR (CDCl₃) δ 1.60-2.10 (m, 5H), 2.18-2.29 (m, 1H), 2.65-2.74 (m, 2H),2.79-2.90 (m, 2H), 3.41-3.59 (m, 2H), 4.03-4.15 (m, 3H), 7.11-7.20 (m,3H), 7.41 (d, 1H, J=7.5 Hz), 7.45-7.63 (m, 2H), 8.06 (m, 1H), 8.31 (dd,1H, J=2.1, 1.8 Hz), 8.51 (d, 1H, J=3.6 Hz), 8.67 (d, 1H, J=2.4 Hz), 9.32(d, 1H, J=1.2 Hz). ¹³C NMR (CDCl₃) δ 21.8, 23.5, 28.2, 29.6, 37.9, 48.5,49.7, 62.0, 122.1, 122.6, 135.1, 137.8, 142.6, 144.8, 147.2, 147.4,156.3, 157.7, 163.4. ES-MS m/z 442 (M+H). Anal. Calcd. forC₂₅H₂₇N₇O.0.3CH₂Cl₂: C, 65.07; H, 5.96; N, 20.99. Found: C, 64.74; H,6.10; N, 20.90.

Example: 165

COMPOUND 165: Preparation of N-{3-[(1H-benzimidazol-2-ylmethyl)-(56,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-guanidine (hydrobromidesalt)

A solution of (3-hydroxypropyl)-carbamic acid tert-butyl ester (0.60 g,3.4 mmol) in anhydrous CH₂Cl₂ (17 mL) was treated with Dess-Martinreagent (1.74 g, 4.1 mmol) for 3 hours at room temperature. The reactionmixture was diluted with Et₂O (30 mL) and washed with a 20% aqueoussolution of sodium thiosulfate (15 mL) followed by a saturated aqueoussolution of sodium bicarbonate (15 mL). The combined aqueous phase wasthen extracted with Et₂O (2×35 mL) and re-washed with 20% sodiumthiosulfate solution (30 mL), saturated NaHCO₃ solution (25 mL), andbrine (25 mL). The organic component was then dried (MgSO₄), filtered,and concentrated under reduced pressure to provide(3-oxopropyl)-carbamic acid tert-butyl ester as a colorless oil (0.54 g,91%).

Using general procedure B,(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.69 g, 2.5 mmol), (3-oxopropyl)-carbamic acid tert-butyl ester (0.54g, 3.1 mmol) and sodium triacetoxyborohydride (0.95 g, 4.5 mmol) werestirred at room temperature in CH₂Cl₂ (13 mL) for 18 hours. Thisyielded, after work-up and column chromatography (5:0.5:94.5MeOH:NH₄OH:CH₂Cl₂), a mixture of desired alkylated product plus productcontaining a boronic acetyl ester group coordinated to the benzimidazole(1.31 g, excess). This was taken forward to the next reaction.

A solution of the above compounds (1.31 g) was dissolved in CH₂Cl₂ (2mL) and treated with trifluoroacetic acid (20 mL) for 2 hours. Thesolution was cooled to 0° C. and diluted with CH₂Cl₂ (50 mL). 10Naqueous NaOH solution (5 mL) was then added slowly until the acidcontent was neutralized and the solution was basic (pH>9). The phaseswere then separated and the aqueous extracted with CH₂Cl₂ (2×50 mL). Thecombined organics were then dried (Na₂SO₄) and concentrated underreduced pressure to give, after column chromatography (10:1:89MeOH:NH₄OH:CH₂Cl₂),N-(1H-benzimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-propane-1,3-diamineas a pale yellow crystalline solid (0.57 g, 68%, 2 steps). ¹H NMR(CDCl₃): δ 1.55-1.85 (m, 3H), 2.10 (br, 1H), 2.25 (q, 1H, J=13.5 Hz),2.54 (t, 1H, J=12.0 Hz), 2.65 (br, 1H), 2.79 (br, 4H), 3.31 (d, 1H,J=12.0 Hz), 3.98 (d, 1H, J=15.0 Hz), 4.00-4.25 (m, 2H), 7.08 (m, 1H),7.16 (m, 2H), 7.40 (d, 1H), J=7.5 Hz), 7.57 (br, 2H), 8.42 (d, 1H, J=4.5Hz), 9.35 (br, 2H).

The above amine (0.14 g, 0.43 mmol) and(tert-butoxycarbonylimino-pyrazol-1-yl-methyl)-carbamic acid tert-butylester (0.13 g, 0.39 mmol) were dissolved in THF (0.4 mL) and stirred for5 hours. The solvent was removed under reduced pressure and CH₂Cl₂ (10mL) was added. The organic phase was washed with a 15% aqueous solutionof NaOH (5×5 mL), dried (Na₂SO₄), and concentrated under reducedpressure. This afforded, after column chromatography (2:0.5:97.5MeOH:NH₄OH:CH₂Cl₂), the di-BOC-protected guanidine adduct as a paleyellow oil (0.18 g, 73%). ¹H NMR (CDCl₃): δ 1.45 (s, 9H), 1.49 (s, 9H),1.66 (m, 3H), 1.85-2.10 (m, 2H), 2.18 (br, 1H), 2.50-2.85 (m, 4H), 3.38(m, 2H), 4.05 (m, 2H), 4.17 (d, 1H, J=15.0 Hz), 7.13 (m, 1H), 7.17 (m,2H), 7.40 (d, 1H, J=7.0 Hz), 7.47 (m, 1H), 7.67 (m, 1H), 8.06 (br, 1H),8.58 (d, 1H, J=4.5 Hz).

Using general procedure D: The above material (176 mg, 0.29 mmol) wasconverted to the hydrobromide salt to provide COMPOUND 165 (152 mg) as awhite solid. ¹H NMR (D₂O) δ 1.69 (m, 2H), 1.80 (m, 1H), 1.98 (q, 1H,J=12.0 Hz), 2.15 (br, 1H), 2.34 (br, 1H), 2.52 (m, 1H), 2.80 (m, 1H),2.97 (br d, 2H, J=4.5 Hz), 3.01 (m, 2H), 4.32 (d, 1H, J=16.5 Hz), 4.48(m, 1H), 4.48 (d, 1H, J=16.8 Hz), 7.56 (m, 2H), 7.76 (m, 2H), 7.83 (m,1H), 8.31 (d, 1H, J=7.8 Hz), 8.59 (d, 1H, J=4.8 Hz). ¹³C NMR (D₂O) δ20.40, 20.49, 27.49, 27.67, 39.10, 48.31, 49.21, 60.60, 114.30 (2C),126.00, 126.96 (2C), 131.05, 139.41, 140.69 (2C), 148.14, 151.13,151.51, 156.93. ES-MS m/z 378 (M+H). Anal. Calcd. forC₂₁H₂₇N₇.3.1HBr.1.5H₂O.0.2C₄H₁₀O: C, 39.07; H, 5.28; N, 14.63; Br,36.96. Found: C, 39.20; H, 5.41; N, 14.69; Br, 36.85.

Example 166

COMPOUND 166: Preparation of{3-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-propyl}-urea(hydrobromide salt)

A solution ofN-(1H-benzimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-propane-1,3-diamine(0.14 g, 0.42 mmol—see preparation ofN-{3-[(1H-benzimidazol-2-ylmethyl)-(S)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-propyl}-guanidine)in isopropanol (2.8 mL) was treated with trimethylsilylisocyanate (80μL, 0.58 mmol) at room temperature. The reaction was stirred 20 hoursand concentrated under reduced pressure. This afforded, after columnchromatography with silica gel (5:1:94 MeOH:NH₄OH:CH₂Cl₂), the desiredurea (37 mg, 23%). ¹H NMR (CDCl₃) δ 1.57 (m, 1H), 1.70-1.85 (m, 3H),2.06 (br, 1H), 2.26 (br, 1H), 2.62 (m, 1H), 2.70-3.00 (m, 4H), 3.38 (br,1H), 3.87 (m, 2H), 4.18 (m, 1H), 4.50 (br, 2H, NH₂), 6.95 (br, 1H, NH),7.18 (m, 3H), 7.46 (d, 1H, J=7.0 Hz), 7.45-7.70 (br, 2H), 8.55 (d, 1H,J=4.0 Hz).

Using general procedure D: The above material (37 mg, 0.10 mmol) wasconverted to the hydrobromide salt to provide COMPOUND 166 (45 mg) as awhite solid. ¹H NMR (D₂O) δ 1.61 (m, 2H), 1.83 (m, 1H), 2.04 (q, 1H,J=10.8 Hz), 2.18 (m, 1H), 2.36 (br, 1H), 2.50 (m, 1H), 2.79 (m, 1H),2.98 (m, 4H), 4.34 (d, 1H, J=16.5 Hz), 4.50 (m, 1H), 4.50 (d, 1H, J=16.5Hz), 7.60 (m, 2H), 7.79 (m, 2H), 7.86 (m, 1H), 8.34 (d, 1H, J=7.2 Hz),8.62 (d, 1H, J=5.1 Hz). ¹³C NMR (D₂O) δ 20.28, 20.37, 27.62, 28.54,37.60, 48.22, 49.16, 60.38, 114.22 (2C), 125.88, 126.90 (2C), 130.95,139.32, 140.58 (2C), 148.02, 151.28, 151.56, 161.67. ES-MS m/z 379(M+H). Anal. Calcd. for C₂₁H₂₆N₆O.2.8HBr.1.6H₂O: C, 39.79; H, 5.09; N,13.26; Br, 35.30. Found: C, 40.13; H, 5.12; N, 12.91; Br,35.09.

Example 167

COMPOUND 167: Preparation of{2-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-ethyl}-urea(hydrobromide salt)

To a solution of 3-aminopropane-1,2-diol (9.92 g, 109 mmol) in THF (350mL) and H₂O (15 mL) was added di-tert-butyldicarbonate (25.0 g, 114mmol). The solution was allowed to stir for 16 h and then concentratedunder reduced pressure. EtOAc (200 mL) was added, and the solution waswashed with saturated aqueous NaHCO₃ solution (100 mL). The aqueousphase was then extracted with EtOAc (2×100 mL), and the organic phasedried (MgSO₄), filtered and concentrated under reduced pressure. Thisgave, after a purification through a plug of silica gel (1:99MeOH/CH₂Cl₂ ramping to 4:96 MeOH/CH₂Cl₂),(2,3-dihydroxy-propyl)-carbamic acid tert-butyl ester (20.2 g, 97%). ¹HNMR (CDCl₃) δ 1.44 (s, 9H), 3.11 (br, 1H, OH), 3.25 (m, 2H), 3.58 (m,2H), 3.74 (m, 1H), 5.03 (br, 1H, NH).

A solution of the above compound (0.28 g, 1.5 mmol) in water (5 mL) wastreated with sodium periodate (0.29 g, 1.4 mmol), stirring for 16 hoursat room temperature. The solution was extracted with CH₂Cl₂ (2×20 mL)and the combined organic phases dried (Na₂SO₄) and concentrated underreduced pressure to afford (2-oxo-ethyl)-carbamic acid tert-butyl ester(0.17 g, 73%).

Using general procedure B,(1H-benzimidazol-2-ylmethyl)-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.11 g, 0.41 mmol), (2-oxo-ethyl)-carbamic acid tert-butyl ester (0.17g, 1.1 mmol) and sodium triacetoxyborohydride (0.17 g, 0.82 mmol) werestirred at room temperature in CH₂Cl₂ (3 mL) for 18 hours. This yielded,after work-up and column chromatography (2:0.5:97.5 MeOH:NH₄OH:CH₂Cl₂),{2-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-ethyl}-carbamicacid tert-butyl ester (0.17g, 100%) which was used in the next reaction.

A solution of the above compound (0.17 g) was dissolved in CH₂Cl₂ (0.5mL) and treated with trifluoroacetic acid (0.5 mL) for 2 hours. CH₂Cl₂(10 mL) was added and the solution was basisified to pH>9 with 15%aqueous NaOH solution (3 mL). The phases were then separated and theaqueous extracted with CH₂Cl₂ (2×5 mL). The combined organics were thendried (Na₂SO₄) and concentrated under reduced pressure to giveN-(1H-benzimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-ethane-1,2-diamine(0.10 g, 76%, 2 steps). ¹H NMR (CDCl₃): δ 1.65-1.95 (m, 3H), 2.02 (br,1H), 2.25 (br, 1H), 2.60-2.90 (m, 5H), 4.05 (m, 2H), 4.17 (d, 1H, J=15.0Hz), 7.14 (m, 3H), 7.42 (d, 1H, J=7.5 Hz), 7.58 (br, 2H), 8.57 (d,1H,J=4.5 Hz).

A solution ofN-(1H-benzimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-ethane-1,2-diamine(0.10 g, 0.31 mmol) in isopropanol (2 mL) was treated withtrimethylsilylisocyanate (60 μL, 0.44 mmol) at room temperature. Thereaction was stirred 20 hours and concentrated under reduced pressure.This afforded, after column chromatography with silica gel (2:0.5:97.5MeOH:NH₄OH:CH₂Cl₂),{2-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-ethyl}-urea(67 mg, 59%). ¹H NMR (CDCl₃) δ 1.68 (m, 1H), 1.86 (m, 1H), 2.02 (br,1H), 2.23 (br, 1H), 2.65 (m, 1H), 2.82 (m, 3H), 3.17 (m, 2H), 4.00 (m,1H), 4.07 (d, 1H, J=15.0 Hz), 4.18 (d, 1H, J=15.0 Hz), 4.43 (br, 2H,NH₂), 6.00 (br, 1H, NH), 7.18 (m, 3H), 7.46 (d, 1H, J=7.0 Hz), 7.45-7.70(br, 2H), 8.55 (d, 1H, J=4.0 Hz).

Using general procedure D: The above material (67 mg, 0.18 mmol) wasconverted to the hydrobromide salt to provide COMPOUND 167 (88 mg) as awhite solid. ¹H NMR (D₂O) δ 1.83 (m, 1H), 2.02 (q, 1H, J=12.8 Hz), 2.15(m, 1H), 2.36 (br, 1H), 2.59 (m, 1H), 2.90-3.10 (m, 4H), 3.26 (m, 1H),4.29 (d, 1H, J=16.2 Hz), 4.46 (d, 1H, J=16.5 Hz), 4.47 (m, 1H), 7.60 (m,2H), 7.79 (m, 2H), 7.86 (m, 1H), 8.33 (d, 1H, J=7.8 Hz), 8.64 (d, 1H,J=5.1 Hz). ¹³C NMR (D₂O) δ 20.41, 20.47, 27.72, 38.81, 47.77, 52.14,60.29, 114.33 (2C), 125.89, 126.99 (3C), 131.03, 139.61, 140.71, 147.92,150.93 (2C), 161.79. ES-MS m/z 365 (M+H). Anal. Calcd. forC₂₀H₂₄N₆O.2.8HBr.1.8H₂O.0.3C₄H₁₀O: C, 39.44; H, 5.21; N, 13.02; Br,34.65. Found: C, 39.33; H, 5.09; N, 12.93; Br, 34.72.

Example 168

COMPOUND 168: Preparation of(3-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-piperidin-1-yl)-(3,5-dichloro-pyridin-4-yl)-methanonePreparation of(3,5-dichloro-pyridin-4-yl)-(3-hydroxymethyl-piperidin-1-yl)-methanone

To a suspension of 3,5-dichloroisonicotinic acid (250 mg, 1.30 mmol) inCH₂Cl₂ (6.5 mL) was added DMF (cat.) and oxalyl chloride (0.45 mL, 5.2mmol), and the mixture was stirred at room temperature for 2 h thenconcentrated in vacuo. To the residue was added THF (2 mL), Et₃N (0.27mL, 1.9 mmol), and a solution of 3-piperidinemethanol (150 mg, 1.30mmol) in THF (4.5 mL), and the mixture was stirred at room temperaturefor 21 h. The mixture was diluted with CH₂Cl₂ (50 mL) and brine (30 mL)and the phases were separated. The organic layer was washed with brine(2×50 mL) and saturated NaHCO₃ (2×50 mL). The organic layer was dried(MgSO₄), filtered, concentrated, and dried in vacuo to afford a crudeoil. Purification of the crude material by column chromatography onsilica gel (100:5:1 CH₂Cl₂/MeOH/NH₄OH) gave a yellow oil (mixture ofisomers) (147 mg, 39%). ¹H NMR (CDCl₃) δ 1.28-1.96 (m, 4H), 2.89-3.26(m, 3H), 3.35-3.45 (m, 1H), 3.50-3.72 (m, 2H), 4.29-4.56 (m, 1H), 8.54(m, 2H).

Preparation of(3,5-dichloro-pyridin-4-yl)-{3-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-piperidin-1-yl}-methanone

To a solution of(3,5-dichloro-pyridin-4-yl)-(3-hydroxymethyl-piperidin-1-yl)-methanone(147 mg, 0.508 mmol) in CH₂Cl₂ (5 mL) was added Dess-Martin periodinane(226 mg, 0.533 mmol) at room temperature. After stirring at roomtemperature for 45 minutes, the mixture was washed with 1 N NaOH(aq)(2×10 mL) then dried (MgSO₄) and concentrated in vacuo to give acolourless oil (121 mg, 83%).

Using General Procedure A: To a stirred solution of the aldehyde fromabove (121 mg, 0.421 mmol) and 5,6,7,8-tetrahydro-quinolin-8-ylamine (75mg, 0.51 mmol) in 4:1 MeOH/trimethyl orthoformate (4.2 mL) was addedNaBH₃CN (106 mg, 1.69 mmol), and the mixture was heated to 60° C. for 21h. Purification of the crude material by column chromatography on silicagel (150:5:1 CH₂Cl₂/MeOH/NH₄OH) gave a colourless oil (mixture ofisomers) (66 mg, 37%). ¹H NMR (CDCl₃) δ 1.24-3.79 (m, 17H), 4.48-4.67(m, 1H), 7.05 (m, 1H), 7.36 (m, 1H), 8.24-8.52 (m, 3H).

A mixture of(3,5-dichloro-pyridin-4-yl)-{3-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-piperidin-1-yl}-methanone(63 mg, 0.15 mmol), 2-chloromethyl-benzimidazole-1-carboxylic acidtert-butyl ester (60 mg, 0.22 mmol), potassium iodide (1 mg, 0.006mmol), and N,N-diisopropylethylamine (0.052 mL, 0.30 mmol) inacetonitrile (3.0 mL) was heated at 60° C. for 16 h. SaturatedNaHCO₃(aq) (10 mL) was added, and the mixture was extracted with CH₂Cl₂(3×12 mL). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. Purification of the crude material by columnchromatography on silica gel (300:5:1 CH₂Cl₂/MeOH/NH₄OH) gave a yellowfoam (79 mg).

A solution of the amine from above (79 mg) in 1:1 TFA/CH₂Cl₂ (4 mL) wasstirred at room temperature for 1 h then concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ (15 mL) and washed with 1 N NaOH(aq) (10mL). The aqueous phase was extracted with CH₂Cl₂ (2×10 mL), and thecombined organic extracts were dried (MgSO₄) and concentrated in vacuoto afford COMPOUND 168 as a yellow foam (mixture of isomers) (72 mg,87%). ¹H NMR (CDCl₃) δ 1.25-4.76 (m, 20H), 7.12-8.64 (m, 9H); 1³C NMR(CDCl₃) δ 21.37, 21.47, 21.75, 22.83, 23.51, 23.87, 24.06, 24.20, 24.87,25.26, 26.90, 27.18, 27.61, 27.94, 29.03, 29.24, 29.45, 29.68, 34.12,34.54, 34.85, 35.53, 38.16, 38.69, 39.37, 42.30, 42.38, 44.48, 45.57,46.22, 47.05, 47.23, 48.61, 49.61, 49.83, 49.97, 51.06, 51.39, 52.89,53.11, 55.30, 59.44, 61.61, 61.85, 62.03, 64.04, 64.26, 111.28, 118.80,121.66, 121.74, 122.29, 128.10, 128.18, 128.35, 128.52, 128.60, 128.68,134.61, 137.35, 137.48, 142.26, 142.43, 146.49, 146.74, 146.99, 147.39,147.59, 147.63, 155.48, 155.70, 156.11, 156.74, 156.90, 157.23, 161.08,161.20. ES-MS m/z 550 (M+H). Anal. Calcd. forC₂₉H₃₀N₆Cl₂O.0.5CH₂Cl₂.0.6H₂O.0.2C₆H₁₄: C, 59.47; H, 5.69; N, 13.55; Cl,17.15. Found: C, 59.62; H, 5.39; N, 13.51; Cl, 16.92.

Example 169

COMPOUND 169: Preparation of(3-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-pyrrolidin-1-yl)-(3,5-dichloro-pyridin-4-yl)-methanonePreparation of carbonic acid 1-benzyl-pyrrolidin-3-ylmethyl ester vinylester

A solution of(1-benzyl-pyrrolidin-3-yl)-methanol (prepared as describedby Y.-H. Wu and R. F. Feldkamp, Pyrrolidines I, 1961, 26, 1519-1524)(455 mg, 2.38 mmol) and vinyl chloroformate (0.40 mL, 4.7 mmol) in1,2-dichloroethane (10 mL) was heated to reflux for 2 h thenconcentrated in vacuo. Purification of the crude material by columnchromatography on silica gel (5% MeOH/CH₂Cl₂) gave a yellow oil (440 mg,71%). ¹H NMR (CDCl₃) δ 1.84 (m, 1H), 2.26 (m, 1H), 3.03 (m, 5H), 4.01(br s, 2H), 4.23 (m, 2H), 4.61 (dd, 1H, J=6.2, 2.3 Hz), 4.93 (dd, 1H,J=14, 2.1 Hz), 7.06 (dd, 1H, J=14, 6.3 Hz), 7.41 (m, 3H), 7.53 (m, 2H).

Preparation of 3-vinyloxycarbonyloxymethyl-pyrrolidine-1-carboxylic acidvinyl ester

A solution of carbonic acid 1-benzyl-pyrrolidin-3-ylmethyl ester vinylester (440 mg, 1.68 mmol) and vinyl chloroformate (0.30 mL, 3.5 mmol) in1,2-dichloroethane (10 mL) was heated to reflux for 6 h thenconcentrated in vacuo. Purification of the crude material by columnchromatography on silica gel (20% EtOAc/hexanes) gave a yellow oil (335mg, 83%). ¹H NMR (CDCl₃) δ 1.68-1.85 (m, 1H), 2.03-2.16 (m, 1H),2.59-2.71 (m, 1H), 3.26 (m, 1H), 3.41-3.52 (m, 1H), 3.55-3.72 (m, 2H),4.11-4.28 (m, 2H), 4.45 (dd, 1H, J=6.3, 1.5 Hz), 4.61 (m, 1H), 4.78 (dd,1H, J=14, 1.5 Hz), 4.94 (m, 1H), 7.08 (m, 1H), 7.22 (dd, 1H, J=14, 6.3Hz).

Preparation of carbonic acid pyrrolidin-3-ylmethyl ester vinyl esterhydrochloride

3-Vinyloxycarbonyloxymethyl-pyrrolidine-1-carboxylic acid vinyl ester(335 mg, 1.39 mmol) was dissolved in CH₂Cl₂ (10 mL), and HCl(g) waspassed through the solution for 2 minutes then the solution wasconcentrated in vacuo. The residue was dissolved in MeOH (10 mL) andheated to reflux for 15 minutes then concentrated in vacuo to give acolourless oil (284 mg, 99%). ¹H NMR (CD₃OD) δ 1.78-1.91 (m, 1H),2.17-2.28 (m, 1H), 2.79 (m, 1H), 3.09 (dd, 1H, J=12, 7.8 Hz), 3.25-3.51(m, 3H), 4.19-4.33 (m, 2H), 4.62 (dd, 1H, J=6.2, 2.0 Hz), 4.89 (m, 1H),7.11 (dd, 1H, J=14, 6.0 Hz).

Preparation of(3,5-dichloro-pyridin-4-yl)-(3-hydroxymethyl-pyrrolidin-1-yl)-methanone

To a suspension of 3,5-dichloroisonicotinic acid (267 mg, 1.39 mmol) inCH₂Cl₂ (7.0 mL) was added DMF (cat.) and oxalyl chloride (0.49 mL, 5.6mmol), and the mixture was stirred at room temperature for 2.5 h thenconcentrated in vacuo. To the residue was added THF (4 mL), Et₃N (0.58mL, 4.2 mmol), and a solution of carbonic acid pyrrolidin-3-ylmethylester vinyl ester hydrochloride (284 mg, 1.37 mmol) in THF (3 mL), andthe mixture was stirred at room temperature for 21 h. The mixture wasdiluted with CH₂Cl₂ (50 mL) and brine (30 mL) and the phases wereseparated. The organic layer was washed with brine (2×50 mL) andsaturated NaHCO₃ (2×50 mL). The organic layer was dried (MgSO₄),filtered, concentrated, and dried in vacuo to afford a yellow oil (315mg).

To a solution of the crude amide from above (315 mg) in MeOH (10 mL) wasadded 10 N NaOH(aq) (1.0 mL, 10 mmol), and the solution was stirred atroom temperature for 30 minutes. Water (15 mL) was added, the mixturewas extracted with CH₂Cl₂ (4×15 mL), and the combined organic extractswere dried (MgSO₄) and concentrated in vacuo. Purification of the crudematerial by column chromatography on silica gel (100:5:1CH₂Cl₂/MeOH/NH₄OH) gave a yellow oil (mixture of isomers) (172 mg, 46%).¹H NMR (CDCl₃) δ 1.44-4.24 (m, 10H), 8.54 (s, 2H).

Preparation of(3,5-dichloro-pyridin-4-yl)-{3-[(S)-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-pyrrolidin-1-yl}-methanone

To a solution of(3,5-dichloro-pyridin-4-yl)-(3-hydroxymethyl-pyrrolidin-1-yl)-methanone(172 mg, 0.625 mmol) in CH₂Cl₂ (6.3 mL) was added Dess-Martinperiodinane (278 mg, 0.655 mmol) at room temperature. After stirring atroom temperature for 40 minutes, the mixture was washed with 1 NNaOH(aq) (2×10 mL) then dried (MgSO₄) and concentrated in vacuo to givea yellow oil (163 mg, 95%).

Using General Procedure A: To a stirred solution of the aldehyde fromabove (163 mg, 0.597 mmol) and 5,6,7,8-tetrahydro-quinolin-8-ylamine(106 mg, 0.715 mmol) in 4:1 MeOH/trimethyl orthoformate (6.0 mL) wasadded NaBH₃CN (150 mg, 2.39 mmol), and the mixture was heated to 60° C.for 15 h. Purification of the crude material by column chromatography onsilica gel (150:5:1 CH₂Cl₂/MeOH/NH₄OH) gave a yellow oil (mixture ofisomers) (86 mg, 36%). ¹H NMR (CDCl₃) δ 1.57-3.96 (m, 16H), 7.06 (m,1H), 7.37 (m, 1H), 8.36 (m, 1H), 8.51 (m, 2H).

A mixture of(3,5-dichloro-pyridin-4-yl)-{3-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-pyrrolidin-1-yl}-methanone(85 mg, 0.21 mmol), 2-chloromethyl-benzimidazole-1-carboxylic acidtert-butyl ester (84 mg, 0.31 mmol), potassium iodide (2 mg, 0.01 mmol),and N,N-diisopropylethylamine (0.073 mL, 0.42 mmol) in acetonitrile (4.2mL) was heated at 60° C. for 24 h. Saturated NaHCO₃(aq) (10 mL) wasadded, and the mixture was extracted with CH₂Cl₂ (3×12 mL). The combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo.Purification of the crude material by column chromatography on silicagel (300:5:1 CH₂Cl₂/MeOH/NH₄OH) gave a yellow oil (124 mg).

A solution of the amine from above (124 mg) in 1:1 TFA/CH₂Cl₂ (4 mL) wasstirred at room temperature for 1 h then concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ (15 mL) and washed with 1 N NaOH(aq) (10mL). The aqueous phase was extracted with CH₂Cl₂ (2×10 mL), and thecombined organic extracts were dried (MgSO₄) and concentrated in vacuoto afford COMPOUND 169 as a yellow foam (mixture of isomers) (94 mg,84%). ¹H NMR (CDCl₃) δ 1.09-4.27 (m, 18H), 7.12-7.25 (m, 3H), 7.43-7.61(m, 3H), 8.11-8.73 (m, 3H); ¹³C NMR (CDCl₃) δ 21.37, 23.37, 23.73,27.80, 28.27, 28.71, 29.16, 36.35, 37.82, 38.65, 44.13, 45.13, 45.41,45.77, 49.18, 49.44, 49.62, 50.06, 50.50, 52.37, 52.89, 53.12, 53.45,61.92, 62.01, 62.38, 62.55, 121.80, 122.37, 122.55, 122.65, 128.04,128.41, 134.35, 134.67, 134.90, 137.41, 137.59, 137.70, 142.99, 146.05,146.59, 147.44, 147.68, 147.77, 155.73, 155.86, 156.56, 157.01, 161.03,161.31. ES-MS m/z 536 (M+H). Anal. Calcd. forC₂₈H₂₈N₆Cl₂O.0.1CH₂Cl₂.1.1H₂O.0.1C₆H₁₄: C, 60.22; H, 5.60; N, 14.68; Cl,13.63. Found: C, 60.11; H, 5.39; N, 14.42; Cl, 13.85.

Example 170

COMPOUND 170: Preparation of4-[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-piperidine-1-carboxamidine(hydrobromide salt)

Using general procedure B,[tert-butoxycarbonylimino-(4-oxo-piperidin-1-yl)-methyl]-carbamic acidtert-butyl ester (490 mg, 1.43 mmol),(5,6,7,8-tetrahydroquinolin-8-yl)-amine (210 mg, 1.43 mmol) and sodiumtriacetoxyborohydride (450 mg, 2.14 mmol) were stirred at roomtemperature in dichloromethane (4 mL) for 16 hours to yield, afterwork-up and column chromatography (2:0.5:97.5 MeOH:NH₄OH:CH₂Cl₂),{tert-butoxycarbonylimino-[4-(5,6,7,8-tetrahydroquinolin-8-ylamino)-piperidin-1-yl]-methyl}-carbamicacid tert-butyl ester as a white solid (560 mg, 82%).

To a solution of the above secondary amine (560 mg, 1.18 mmol),2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (470 mg,1.77 mmol), and potassium iodide (10 mg, 0.06 mmol) in anhydrous CH₃CN(12 mL) was added diisopropylethylamine (0.41 mL, 2.35 mmol) and thereaction stirred at 40° C. for 16 hours. The mixture was thenconcentrated under reduced pressure and the residue partitioned betweenCH₂Cl₂ (30 mL) and brine (15 mL). The organic phase was separated andthe aqueous phase was extracted with CH₂Cl₂ (2×15 mL). The combinedorganic phases were then dried (Na₂SO₄), filtered, and concentratedunder reduced pressure to give a crude residue that was purified byradial chromatography with silica gel (saturated NH₃/Et₂O). This gave2-{[[1-(tert-butoxycarbonylimino-tert-butoxycarbonyliminomethyl)-piperidin-4-yl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester as a pale yellow oil (336 mg, 40%). ¹H NMR (CDCl₃)δ 1.45 (s, 9H), 1.48 (s, 9H), 1.62 (br, 3H), 1.66 (s, 9H), 1.77 (m, 3H),2.03 (m, 4H), 2.56 (m, 1H), 2.72 (m, 1H), 2.90 (br t, 2H, J=12.0 Hz),3.15 (br t, 1H), 4.22 (m, 1H), 4.34 (d, 1H, J=15.0 Hz), 4.48 (d, 1H,J=15.0 Hz), 6.85 (m, 1H), 7.10 (d, 1H, J=7.8 Hz), 7.24 (m, 2H), 7.64 (m,1H), 7.75 (m, 1H), 8.31 (d, 1H, J=5.4 Hz), 10.09 (s, 1H, NH).

Using general procedure D: A portion of the above material (75 mg, 0.11mmol) was converted to the hydrobromide salt to provide COMPOUND 170 (58mg) as a white solid. ¹H NMR (D₂O) δ 1.60-2.00 (m, 4H), 2.05-2.25 (m,3H), 2.42 (m, 1H), 2.90-3.15 (m, 5H), 3.68 (m, 2H), 4.42 (d, 1H, J=16.8Hz), 4.53 (m, 1H), 4.56 (d, 1H, J=16.8 Hz), 7.58 (m, 2H), 7.70-7.85 (m,3H), 8.26 (d, 1H, J=7.5 Hz), 8.54 (d, 1H, J=5.4 Hz). ¹³C NMR (D₂O) δ20.69, 23.95, 27.54, 29.01, 30.59, 43.81, 45.51, 45.58, 58.32, 58.71,114.24 (2C), 125.85, 127.01 (2C), 131.02, 139.19, 140.53 (2C), 148.02,151.32, 151.75, 156.21. ES-MS m/z 404 (M+H). Anal. Calcd. forC₂₃H₂₉N₇.3.0HBr.2.0H₂O: C, 40.49; H, 5.32; N, 14.37; Br, 35.13. Found:C, 40.57; H, 5.33; N, 14.15; Br, 35.25.

Example 171

COMPOUND 171: Preparation of4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-piperidine-1-carboxylicacid amide (hydrobromide salt)

4-Hydroxypiperidine (2.58 g, 25.5 mmol) was dissolved in THF (100 mL)and treated with di-tert-butyl dicarbonate (5.57 g, 25.5 mmol) andstirred for 40 minutes at room temperature. The solvent was removedunder reduced pressure to afford 4-hydroxypiperidine-1-carboxylic acidtert-butyl ester as a light yellow oil that was used in the nextreaction.

A solution of the above alcohol (0.79 g, 3.9 mmol) in CH₂Cl₂ (20 mL) wastreated with molecular seives (1.95 g), N-methylmorpholine oxide (0.69g, 5.9 mmol), and TPAP (0.14 g, 0.40 mmol). The mixture was stirred for2 hours at room temperature and then filtered through a plug of silicagel, eluting with Et₂O. The filtrate was then concentrated under reducedpressure to afford the desired 4-oxopiperidine-1-carboxylic acidtert-butyl ester (0.69 g, 89%). ¹H NMR (CDCl₃) δ 1.49 (s, 9H), 2.44 (t,4H, J=7.0 Hz), 3.72 (t, 4H, J=7.0 Hz).

Using general procedure B, 4-oxopiperidine-1-carboxylic acid tert-butylester (0.69 g, 3.4 mmol), (5,6,7,8-tetrahydroquinolin-8-yl)-amine (0.51g, 3.4 mmol) and sodium triacetoxyborohydride (1.10 g, 5.2 mmol) werestirred at room temperature in dichloromethane (20 mL) for 16 hours toyield, after work-up and column chromatography with silica gel(5:0.5:94.5 MeOH:NH₄OH:CH₂Cl₂),4-(5,6,7,8-tetrahydroquinolin-8-ylamino)-piperidine-1-carboxylic acidtert-butyl ester as a white solid (1.00 g, 87%).

To a solution of4-(5,6,7,8-tetrahydroquinolin-8-ylamino)-piperidine-1-carboxylic acidtert-butyl ester (1.00 g, 3.0 mmol),2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (1.20 g,4.5 mmol), and potassium iodide (25 mg, 0.15 mmol) in anhydrousacetonitrile (30 mL) was added diisopropylethylamine (1.05 mL, 6.0 mmol)and stirred at 40° C. for 16 hours. The mixture was then concentratedunder reduced pressure and the residue partitioned betweendichloromethane (30 mL) and brine (25 mL). The organic phase wasseparated and the aqueous phase was extracted with dichloromethane (2×25mL). The combined organic phases were then dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to give a crude residue that waspurified by column chromatography with silica gel (2:0.5:97.5MeOH:NH₄OH: CH₂Cl₂). This afforded2-{[(1-tert-butoxycarbonyl-piperidin-4-yl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester as an light orange solid (0.50 g, 30%).

A solution of the above compound (0.50 g, 0.9 mmol) was dissolved inCH₂Cl₂ (2 mL) and treated with trifluoroacetic acid (2.5 mL) for 1 hour.CH₂Cl₂ (20 mL) was added and the solution was basisified to pH>9 with15% aqueous NaOH solution (10 mL). Brine (20 mL) was added to alleviateemulsification. The phases were then separated and the aqueous extractedwith CH₂Cl₂ (2×40 mL). The combined organics were then dried (Na₂SO₄)and concentrated under reduced pressure to give(1H-benzimidazol-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(0.32 g, 100%). ¹H NMR (CDCl₃): δ 1.35 (m, 1H), 1.50-1.50-1.75 (m, 3H),1.84 (m, 2H), 2.05 (br, 1H), 2.23 (br, 1H), 2.40-2.65 (m, 3H), 2.74 (m,1H), 2.80-2.95 (m, 2H), 3.07 (m, 1H), 4.13 (m, 1H), 4.21 (s, 2H), 7.16(m, 3H), 7.43 (d, 1H, J=7.5 Hz), 7.44 (br, 1H), 7.67 (br, 1H), 8.59 (d,1H, J=4.5 Hz).

A solution of(1H-benzimidazol-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(0.16 g, 0.43 mmol) in isopropanol (3 mL) was treated withtrimethylsilylisocyanate (81 μL, 0.60 mmol) at room temperature. Thereaction was stirred 20 hours and concentrated under reduced pressure.This afforded, after column chromatography with silica gel (5:0.5:94.5MeOH:NH₄OH:CH₂Cl₂),4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-piperidine-1-carboxylicacid amide (112 mg, 66%). ¹H NMR (CDCl₃) δ 1.42 (m, 1H), 1.60-1.95 (m,5H), 2.02 (br, 1H), 2.24 (br, 1H), 2.60-2.80 (m, 4H), 2.89 (m, 1H), 3.70(br, 1H), 4.03 (br, 1H), 4.15 (m, 3H), 4.39 (br, 2H, NH₂), 7.18 (m, 3H),7.45 (d, 1H, J=7.5 Hz), 7.66 (br, 2H), 8.59 (d, 1H, J=4.0 Hz).

Using general procedure D: The above material (105 mg, 0.26 mmol) wasconverted to the hydrobromide salt to provide COMPOUND 171 (107 mg) as awhite solid. ¹H NMR (D₂O) δ 1.56 (dqt, 2H, J=2.1, 12.0 Hz), 1.82 (br,2H), 2.14 (br, 3H), 2.42 (br, 1H), 2.77 (br t, 2H, J=12.3 Hz), 2.97 (br,3H), 3.92 (br t, 2H, J=17.1 Hz), 4.42 (d, 1H, J=16.8 Hz), 4.54 (m, 1H),4.57 (d, 1H, J=16.8 Hz), 7.59 (m, 2H), 7.75 (m, 2H), 7.79 (m, 1H), 8.28(d, 1H, J=8.1 Hz), 8.55 (d, 1H, J=5.7 Hz). ³C NMR (D₂O) δ 20.71, 23.89,27.55, 29.45, 31.09, 43.98 (3C), 58.88, 58.97, 114.21 (2C), 125.83,127.03 (2C), 130.90, 139.11, 140.49 (2C), 148.02, 151.55, 151.96,160.13. ES-MS m/z 405 (M+H). Anal. Calcd. forC₂₃H₂₈N₆O.3.0HBr.1.3H₂O.0.3C₄H₁₀O: C, 41.95; H, 5.32; N, 12.13; Br,34.60. Found: C, 42.08; H, 5.30; N, 12.19; Br, 34.52.

Example 172 Assay for Inhibition of HIV-1 (NL4.3) Replication in PBMC's

Inhibition of HIV-1 NL4.3 replication assays in PBMC's (peripheral bloodmononuclear cells) were performed as previously described (De Clercq etal. Proc. Natl. Acad. Sci, 1992, 89, 5286-5290; De Clercq et al.Antimicrob. Agents Chemother. 1994, 38, 668-674; Schols, D. et al. J.Exp. Med. 1997, 186, 1383-1388). Briefly, PBMC's from healthy donorswere isolated by density gradient centrifugation and stimulated with PHAat 1 μg/ml (Sigma Chemical Co., Bomem, Belgium) for 3 days at 37° C. Theactivated cells (PHA-stimulated blasts) were washed three times withPBS, and viral infections were performed as described by Cocchi et al.(Science 1995, 270, 1811-1815). HIV-infected or mock-infectedPHA-stimulated blasts were cultured in the presence of 25 U/mL of IL-2and varying concentrations of test compounds. Supernatant was collectedat days 6 and 10, and HIV-1 core antigen in the culture supernatant wasanalyzed by the p24 ELISA kit (DuPont-Merck Pharmaceutical Co,Wilmington, Del.). The 50% inhibitory concentration (IC₅₀) was definedas the concentration of test compound required to inhibit p24 antigenproduction by 50%.

When tested in the assay described above, many compounds of theinvention exhibited IC₅₀'s in the range 5 nM-5.5 nM.

Assay for Inhibition of SDF-1α Induced Ca Flux in CEM Cells

Inhibition of SDF-1 induced calcium flux was assayed using CCRF-CEMcells, a T-lymphoblastoid cell line which expresses CXCR4. CCRF-CEMcells (5×10⁶ cells/mL in RPMI 1640 medium containing 2% foetal bovineserum) were pre-loaded with 1 μM Fluo-4 fluorescent calcium indicatordye and incubated at 37° C. for 40 minutes. The loaded cells were washedand resuspended in buffer containing 20 mM HEPES pH 7.4, 1× HanksBalanced Salt Solution (HBSS), 0.2% bovine serum albumin, 2.5 mMprobenecid and plated out in 96 well tissue culture plates at 3.5×10⁵cells per well. The cells were incubated with test compound, or buffercontrol, for 15 minutes at 37° C. Calcium flux was stimulated byaddition of 25 nM SDF-1 and fluorescence measured using a FLEXstationfluorescence plate reader (Molecular Devices). lonomycin was added 80seconds after addition of SDF-1 in order to measure total calciumloading. Compounds were tested at a concentration range of 2000-0.128nM. Fluorescence measurements were normalised with respect to untreatedcontrols. The 50% inhibitory concentration (IC₅₀ value) was defined asthe concentration of test compound required to inhibit SDF-1-inducedcalcium flux by 50% relative to unteated controls.

When tested in the assay described above, the compounds of the inventionexhibited IC₅₀s in the range 5 nM-5 μM.

Example 173 Elevation of Mouse Progenitor Cell Levels

The effects of subcutaneous (s.c.) administration of1,1′-[1,4-phenylene-bis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane(AMD3100) to C3H/H3 J mice on numbers of granulocyte macrophage(CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitorcells per mL of blood were measured. Progenitors were stimulated to formcolonies in vitro with the combination of 1 U/ml rhu Epo, 50 ng/ml rhuSLF, 5% ^(Vol)/_(Vol) pokeweed mitogen mouse spleen cell conditionedmedium (PWMSCM), and 0.1 mM hemin. Plates were scored 7 days afterincubation.

The time dependent effects on the number of progenitors mobilized withAMD3100 are for a single s.c. injection of 5 mg/Kg and are shown inTable 1. TABLE 1 Absolute Progenitors Per ML Blood MethylcelluloseCulture CFU-GM BFU-E CFU-GEMM Control 289.8 49.4 25.8 AMD3100: 15″ 791.6134.5 90.4 AMD3100: 30″ 1805.5 209.3 113.5 AMD3100: 120″ 828.7 102.347.6

To measure the dose-dependent effects, AMD3100 was administered at 1,2.5, 5 and 10 mg/Kg via a single s.c. injection and the number ofprogenitors per mL of blood was measured at 1 hour post administration,and the results are shown in Table 2. TABLE 2 Absolute NumberProgenitors Per ML Blood Methylcellulose Culture CFU-GM BFU-E CFU-GEMMSaline 188.1 16 19 AMD3100: 10 mg/kg 825.6 120.5 79.8 AMD3100: 5 mg/kg608.4 92.8 69.5 AMD3100: 2.5 mg/kg 687.6 98.9 70.6 AMD3100: 1 mg/kg 42462 27.1

Fold Change Compared to Time 0 Progenitors Methylcellulose Culture TimeGM BFU-E CFU-GEMM 15″ 2.73 2.72 3.51 30″ 6.23 4.24 4.41  2′ 2.86 2.071.85

Maximum mobilization of mouse progenitors is achieved at a dose of 2.5to 10 mg/kg AMD3100, approximately 0.5 to 1 hour after injection, asshown in Table 3. The compounds of the invention behave in a mannersimilar to AMD3100.

Example 174 Mobilization of Mouse Progenitor Cells in Combination withMIP-1α and G-CSF

The progenitor cell mobilization capacity of AMD3100 in combination withmouse (mu) macrophage inflammatory protein (MIP-1α) was tested with orwithout prior administration of rhu G-CSF. MIP-1α has been previouslyshown to mobilize progenitor cells in mice and humans (Broxmeyer, H. E.,et al., Blood Cells, Molecules, and Diseases (1998) 24(2): 14-30).

Groups of mice were randomized to receive control diluent (saline) orG-CSF at a dose of 2.5 μg per mouse, twice a day, for two days via s.c.injection. Eleven hours after the final injection of saline or G-CSF,the mice were divided into groups to receive MIP-1α administered I.V. ata total dose of 5 μg, AMD3100 administered s.c. at a dose of 5 mg/Kg, ora combination of both MIP-1α and AMD3100 at the same doses. One hourlater, the mice were sacrificed and the number of progenitor cells permL of blood were measured. These data are summarized in FIG. 1.

AMD3100 acts in an additive to greater than additive manner formobilization of progenitor cells when used in combination with mouse(mu) macrophage inflammatory protein (MIP)-1α, each given 11 hours afterthe addition of rhu G-CSF or control diluent (saline) and 1 hour priorto assessing the blood. The compounds of the invention behave in amanner similar to AMD3100.

Example 175 Clinical Elevation of Progenitor Cell Levels

Five healthy human volunteers having initial white blood cell counts of4,500-7,500 cells/mm³ were used in the study. Each patient was given asingle subcutaneous (s.c.) injection of 80 μg/kg AMD3100 (i.e.,1,1′-[1,4-phenylene-bis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane)in 0.9% saline, from a stock solution of 10 mg/mL AMD3100 in saline,under sterile conditions. Blood samples were obtained via catheter priorto the dose, and at various times up to 24 hours after dosing.

The blood samples were evaluated for total white blood cells, CD34positive progenitor cells (via FACS analysis) as a percentage of totalwhite blood cells, as well as the absolute numbers per mL and cyclingstatus of granulocyte macrophage (CFU-GM), erythroid (BFU-E), andmultipotential (CFU-GEMM) progenitor cells.

As shown in Tables 3 and 4, administration of AMD3100 caused anelevation of the white blood cell count and of CD34 positive progenitorcells in human volunteers which maximized at 6 hourspost-administration. TABLE 3 AMD3100 induced mobilization of white bloodcells in individual volunteers (×10³ WBC's). TREATMENT Base- Day IDScreen line 30 Min 1 Hr 2 Hr 4 Hr 6 Hr 9 Hr 2 P1 7.4 6.41 8.02 14.8 21.423.2 26.2 22.3 7.07 P2 6.04 5.45 6.53 8.93 13.5 18.00 19.2 19.6 8.03 P34.38 5.8 7.14 9.28 ND 18.10 17.9 18.4 4.98 P4 5.08 5.31 4.37 7.38 12.414.6 15.8 13.9 4.98 P5 4.53 5.02 6.08 8.43 ND 16.90 19.3 19.00 4.57

TABLE 4 AMD3100 induced mobilization of CD34 positive cells, expressedas the percentage of the total WBC's in individual volunteers. TREATMENTID Baseline 1 Hr 3 Hr 6 Hr 9 Hr Day 2 P1 .07 .04 .07 .11 .11 .08 P2 .08.06 .08 .13 .11 .12 P3 .07 .16 .06 ND .11 .07 P4 .05 .07 .09 .09 .1 .1P5 .12 .12 .13 .2  .2 .16

The blood was also analyzed for AMD3100 mobilized these progenitors.

Absolute numbers of unseparated and low density (Fico-hypaque separated)nucleated cells per ml of blood, as well as the absolute numbers per mland cycling status of granulocyte macrophage (CFU-GM), erythroid(BFU-E), and multipotential (CFU-GEMM) progenitor cells were measured innormal donors injected s.c. with AMD3100. The above parameters wereassessed prior to injection and at 1, 3, 6, 9 and 24 hours afterinjection of AMD3100. All progenitor cell results are based on thescoring of 3 culture plates per assay per point.

For the progenitor cell numbers and cycling status, the numbers ofCFU-GM, BFU-E and CFU-GEMM in methylcellulose cultures by stimulation ofthe cells with 1 Unit (U)/ml recombinant human (rhu) erythropoietin, 100U/ml rhu granulocyte-macrophage colony stimulating factor (GM-CSF), 100U/ml rhu interleukin-3 (IL-3) and 50 ng/ml rhu steel factor (SLF=stemcell factor (SCF)). The CFU-GM were also evaluated in agar culturesstimulated with 100 U/ml rhu GM-CSF and 50 ng/ml rhu SLF. For both typesof assays, colonies were scored after 14 day incubation in a humidifiedatmosphere with 5% CO₂ and lowered (5%) O₂ tension. Cell cycling statusof progenitors was measured using a high specific activity tritiatedthymidine kill technique as previously described (Broxmeyer, H. E., etal., Exp. Hematol. (1989) 17:455-459).

The results are given first, as the mean fold change in absolute numbersof nucleated cells and progenitors at 1, 3, 6, 9 and 24 hours comparedto the preinjection (=Time (T) 0) counts for all five donors, as seen inTables 5-7.

In the tables below,

-   -   STD—Standard deviation    -   STE—Standard error    -   PBL-US—peripheral blood-unseparated    -   PBL-LD—peripheral blood-low density (Ficoll Separated)

P—Significance using a 2 tailed t test TABLE 5 Fold Change Compared toTIME = 0 (Average of 5 donors) NUCLEATED CELLULARITY PBL-US PBL-LD MEANSTD STE % CHG P MEAN STD STE % CHG P T = 0 1.00 0.00 0.00 0.0% 1.00 0.000.00 0.0% T = 1 1.69 0.00 0.00 68.6% 0.017 1.86 0.00 0.00 86.2% 0.000 T= 3 2.80 0.51 0.23 180.2% 0.000 2.86 0.28 0.12 185.6% 0.000 T = 6 3.260.61 0.27 225.8% 0.000 3.66 0.43 0.19 266.3% 0.001 T = 9 3.09 0.69 0.31209.4% 0.000 3.64 1.18 0.53 264.3% 0.001 T = 24 1.07 0.65 0.29 7.0%0.553 1.05 1.19 0.53 4.6% 0.815

TABLE 6 METHYLCELLULOSE CULTURE CFU-GM BFU-E CFU-GEMM MEAN STD STE % CHGP MEAN STD STE % CHG P MEAN STD STE % CHG P T = 0 1.00 0.00 0.00 0.0%1.00 0.00 0.00 0.0% 1.00 0.00 0.00 0.0% T = 1 4.77 0.00 0.00 376.7%0.001 1.99 0.00 0.00 98.9% 0.002 2.32 0.00 0.00 131.8% 0.000 T = 3 13.661.56 0.70 1266.5% 0.001 3.21 0.50 0.22 221.3% 0.004 4.33 0.44 0.20332.5% 0.000 T = 6 21.71 5.78 2.58 2070.6% 0.000 6.01 1.25 0.56 500.5%0.006 10.07 0.59 0.27 907.2% 0.002 T = 9 10.47 5.09 2.28 947.3% 0.0004.34 2.99 1.34 334.4% 0.000 5.25 4.54 2.03 425.4% 0.014 T = 24 1.56 3.011.34 55.5% 0.005 1.26 1.02 0.45 26.3% 0.194 1.53 3.04 1.36 53.2% 0.199

TABLE 7 AGAR CULTURE CFU-GM MEAN STD STE % CHG P T = 0 1.00 0.00 0.000.0% T = 1 2.81 0.00 0.00 180.8% 0.001 T = 3 8.54 0.75 0.34 754.1% 0.000T = 6 17.93 1.62 0.72 1692.8% 0.000 T = 9 10.25 4.57 2.04 924.9% 0.000 T= 24 2.08 2.06 1.03 108.3% 0.073

The results are then shown as a fold change from T=0 levels for eachindividual donor, as shown in Tables 8-10. TABLE 8 FOLD CHANGE COMPAREDTO TIME = 0 for each individual patient (P) NUCLEATED CELLULARITY PBL-USPBL-LD P1 P2 P3 P4 P5 P1 P2 P3 P4 P5 T = 0 1.00 1.00 1.00 1.00 1.00 1.001.00 1.00 1.00 1.00 T = 1 2.54 1.38 1.38 1.36 1.76 2.07 1.99 1.48 1.662.10 T = 3 3.55 2.74 2.02 2.46 3.23 2.83 3.25 2.17 2.82 3.20 T = 6 3.972.94 2.74 2.60 4.04 4.07 3.90 2.27 2.78 5.30 T = 9 3.27 3.30 2.69 2.243.96 3.65 4.43 2.47 2.48 5.17 T = 24 1.21 1.43 0.96 0.77 0.99 1.01 1.710.79 0.60 1.12

TABLE 9 PROGENITORS METHYL CELLULOSE CULTURE CFU-GM BFU-E CFU-GEMM P1 P2P3 P4 P5 P1 P2 P3 P4 P5 P1 P2 P3 P4 P5 T = 0 1.00 1.00 1.00 1.00 1.001.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 T = 1 5.09 5.33 3.706.87 2.84 2.58 1.48 2.30 1.46 2.13 2.07 2.26 2.22 1.96 3.07 T = 3 7.1217.02 15.07 20.72 8.40 5.13 1.98 2.61 2.60 3.75 4.25 3.47 4.34 5.14 4.43T = 6 14.66 23.96 20.99 28.54 20.39 9.14 3.67 4.54 3.34 9.35 7.47 9.356.52 9.10 17.92 T = 9 6.26 12.51 9.42 14.08 10.09 5.43 4.61 3.71 2.935.05 2.64 7.09 2.47 4.52 9.55 T = 24 1.10 1.91 1.43 1.51 1.83 1.06 1.881.14 0.79 1.44 1.12 2.62 0.69 0.98 2.25

TABLE 10 AGAR CULTURE CFU-GM P1 P2 P3 P4 P5 T = 0 1.00 1.00 1.00 1.001.00 T = 1 3.05 3.74 1.67 2.71 2.87 T = 3 8.88 9.49 7.47 10.46 6.40 T =6 17.77 24.01 14.04 13.07 20.75 T = 9 10.28 7.72 10.22 12.78 T = 24 3.691.13 1.30 2.20

The actual nucleated cell and progenitor cell numbers per ml of bloodand the cycling status (=% progenitors in DNA synthesis (S) phase of thecell cycle) of progenitors for each of the five donors (#'s P1, P2, P3,P4, and P5) is shown in Tables 11 and 12. TABLE 11 BFU-E P1 CFU-GEMMCFU-GM Absolute # Absolute # Absolute # of Cycling of Cycling of CyclingProgenitors Status of Progenitors Status of Progenitors Status of per

L Progenitors per

L Progenitors per

L Progenitors T = 0 247 6% 261 0% 127 6% T = 1 1259 1% 674 0% 264 0% T =3 1760 1% 1340 13% 540 7% T = 6 3624 0% 2388 0% 949 0% T = 9 1547 2%1418 11% 335 0% T = 24 271 0% 278 0% 142 0% CFU-GM BFU-E P2 Absolute #Absolute # CFU-GEMM of Cycling of Cycling Absolute # of CyclingProgenitors Status of Progenitors Status of Progenitors Status of per

L Progenitors per

L Progenitors per

L Progenitors T = 0 273 0% 410 2% 120 0% T = 1 1455 0% 608 3% 272 6% T =3 4646 2% 809 0% 418 0% T = 6 6540 0% 1502 0% 1126 0% T = 9 3416 0% 18860% 854 4% T = 24 521 3% 768 2% 316 0% BFU-E P3 CFU-GEMM CFU-GM Absolute# Absolute # Absolute # of Cycling of Cycling of Cycling ProgenitorsStatus of Progenitors Status of Progenitors Status of per

L Progenitors per

L Progenitors per

L Progenitors T = 0 281 0% 351 0% 140 0% T = 1 1040 0% 806 0% 312 0% T =3 4233 1% 915 0% 610 0% T = 6 5895 0% 1593 0% 916 0% T = 9 2647 0% 13020% 347 0% T = 24 402 0% 402 0% 97 0% CFU-GM BFU-E P4 Absolute # Absolute# CFU-GEMM CFU-GEMM of Cycling of Cycling Absolute # of CyclingProgenitors Status of Progenitors Status of Progenitors Status of per

L Progenitors per

L Progenitors per

L Progenitors T = 0 138 0% 460 0% 101 0% T = 1 947 0% 672 0% 199 0% T =3 2857 5% 1195 9% 519 0% T = 6 3936 0% 1533 0% 920 8% T = 9 1942 0% 13480% 457 0% T = 24 208 5% 362 3% 99 0% BFU-E P5 CFU-GEMM CFU-GM Absolute #Absolute # Absolute # of Cycling of Cycling of Cycling ProgenitorsStatus of Progenitors Status of Progenitors Status of per

L Progenitors per

L Progenitors per

L Progenitors T = 0 169 0% 343 1% 55 0% T = 1 481 0% 730 0% 169 0% T = 31423 5% 1288 3% 244 0% T = 6 3454 0% 3208 1% 987 0% T = 9 1710 0% 17310% 526 0% T = 24 310 0% 495 0% 124 0%

TABLE 12 AGAR Culture AGAR Culture AGAR Culture AGAR Culture AGARCulture CFU-GM CFU-GM CFU-GM CFU-GM CFU-GM P1 P2 P3 P4 P5 Absolute #Absolute # Absolute # Absolute # Absolute # Cycling of Cycling ofCycling of Cycling of Cycling of Status of Progenitors Status ofProgenitors Status of Progenitors Status of Progenitors Status ofProgenitors Progen- per

L Progenitors per

L Progenitors per

L Progenitors per

L Progenitors per

L itors T = 0 233 6% 100 0% 140 0% 124 0% 104 0% T = 1 710 0% 376 0% 2340% 336 0% 298 3% T = 3 2070 0% 953 1% 1049 0% 1299 0% 664 0% T = 6 41420% 2409 3% 1972 3% 1623 0% 2153 1% T = 9 1032 0% 1085 0% 1268 0% 1326 0%T = 24 371 0% 159 0% 162 0% 229 0%

The results for all five donors were very consistent with maximal foldincreases in circulating levels of progenitor cells seen 6 hours afterinjection of AMD3100 into the human donor subjects. Progenitors were ina slow or non-cycling state prior to and 1, 3, 6, 9 and 24 hours afterinjection of AMD3100. The compounds of the invention behave in a mannersimilar to AMD3100.

Example 176 Mobilized Bone Marrow Stem Cells for Myocardial Repair

Adult rats are anesthetized and a thoracotomy is performed. Thedescending branch of the left coronary artery is ligated and notreperfused. Within 4 to 6 hours after ligation the animals are injectedwith limit dilution AMD-3100 or AMD-3100 plus rhG-CSF. Control rats arenot treated with the reagents. The animals are monitored at one-weekintervals by echocardiography and MRI. The experiment is terminated at2, 6 to 12 weeks post-surgery. On the day of sacrifice, the hemodynamicfunctions are analyzed for left ventricle-end diastolic pressure, leftventricle-developed pressure and the rate of rise and fall of leftventricle pressure. The heart is then arrested in diastole and perfusedvia the abdominal aorta to flush residual blood from the vascularnetwork of the myocardium. This is followed by perfusion of the heartwith 10% formalin. Several slices are made through the fixed heart andthese are embedded in paraffin and sections. The sections are stainedand analyzed by light microscopy to determine the size of the infarct inthe treated and control animals. Tissue sections from hearts taken at 2weeks after surgery are stained with antibodies specific for immature,developing myocyte and blood vessel proteins and analyzed by confocalmicroscopy. The immunohistochemical analysis involves the identificationof transcription factors and surface markers expressed in early stagesof myocyte development. The results of this experiment will show thatwhen the reagent AMD-3100 is administered within hours after inductionof cardiac ischemia, together with or without rhG-CSF, this reagentmobilizes bone marrow stem cells rapidly, and will result in a block tocardiac remodeling and scar formation and will lead to regeneration ofthe dead myocardium. The compounds of the invention behave in a mannersimilar to AMD3100.

1. A compound of the formula:

or the salts or pro-drug forms thereof; and including any stereoisomericforms thereof; X and Y are independently N or CR¹; Z is S, O, NR¹ or CR¹₂; each R¹—R⁶ is independently H or a noninterfering substituent; n1 is0-4; n2 is 0-1, wherein the * signifies C≡C may be substituted forCR⁵═CR⁵; n3 is 0-4; wherein n1+n2+n3 is greater than or equal to 2;bis0-2; wherein the following combinations of R groups may be coupled togenerate a ring, which ring may be saturated or unsaturated: R²+R² oneR²+R³ R³+ one R⁴, R⁴+R⁴, one R⁵+ another R⁵, one R⁵+ one R⁶, and R⁶+R⁶;wherein the ring may not be aromatic when the participants in ringformation are two R⁵; and wherein when n2 is 1, neither n1 nor n3 can be0.
 2. The compound of claim 1 wherein each of R¹ to R⁶ is independentlyH or a noninterfering substituent which is alkyl (C₁₋₁₀), alkenyl(C₂₋₁₀), alkynyl (C₂₋₁₀), aryl (“C”₅₋₁₂), arylalkyl, arylalkenyl, orarylalkynyl, each of which may optionally contain one or moreheteroatoms selected from O, S, and N and each of which may further besubstituted; or optionally substituted forms of acyl, arylacyl,alkyl-alkenyl-, alkynyl- or arylsulfonyl and forms thereof which containheteroatoms in the alkyl, alkenyl, alkynyl or aryl moieties; or which isOR, SR, NR₂, COOR, CONR₂, where R is H or optionally substituted alkyl,alkenyl, alkynyl or aryl as defined above; and wherein, when thesubstituted atom is C, the noninterfering substituent may be halo, OOCR,NROCR, where an R is H or a substituent set forth above, or may be ═O.3. The compound of claim 1 wherein said compound is of the formula

or the salts or pro-drug forms thereof; and including any stereoisomericforms thereof; wherein R¹—R⁶ and n1-n3 are as defined for Formula I. 4.The compound of claim 3 wherein each of R¹ to R⁶ is independently H or anoninterfering substituent which is alkyl (C₁₋₁₀), alkenyl (C₂₋₁₀),alkynyl (C₂₋₁₀), aryl (“C”₅₋₁₂), arylalkyl, arylalkenyl, or arylalkynyl,each of which may optionally contain one or more heteroatoms selectedfrom O, S, and N and each of which may further be substituted; oroptionally substituted forms of acyl, arylacyl, alkyl-alkenyl-, alkynyl-or arylsulfonyl and forms thereof which contain heteroatoms in thealkyl, alkenyl, alkynyl or aryl moieties; or which is OR, SR, NR₂, COOR,CONR₂, where R is H or optionally substituted alkyl, alkenyl, alkynyl oraryl as defined above; and wherein, when the substituted atom is C, thenoninterfering substituent may be halo, OOCR, NROCR, where an R is H ora substituent set forth above, or may be =O.
 5. The compound of claim 1wherein said compound is of the formula

or the salts or pro-drug forms thereof; and including any stereoisomericforms thereof; wherein d is 0-3, the dotted line represents an optionalπ bond and R¹—R⁶ are defined as in claim
 1. 6. The compound of claim 5wherein each of R¹ to R⁶ is independently H or a noninterferingsubstituent which is alkyl (C₁₋₁₀), alkenyl (C₂₋₁₀), alkynyl (C₂₋₁₀),aryl (“C”₅₋₁₂), arylalkyl, arylalkenyl, or arylalkynyl, each of whichmay optionally contain one or more heteroatoms selected from O, S, and Nand each of which may further be substituted; or optionally substitutedforms of acyl, arylacyl, alkyl-alkenyl-, alkynyl- or arylsulfonyl andforms thereof which contain heteroatoms in the alkyl, alkenyl, alkynylor aryl moieties; or which is OR, SR, NR₂, COOR, CONR₂, where R is H oroptionally substituted alkyl, alkenyl, alkynyl or aryl as defined above;and wherein, when the substituted atom is C, the noninterferingsubstituent may be halo, OOCR, NROCR, where an R is H or a substituentset forth above, or may be =O.
 7. The compound of claim 1 wherein saidcompound is of the formula

or the salts or pro-drug forms thereof; and including any stereoisomericforms thereof; wherein d is 0-3, the dotted line is an optional π bond,and R¹—R⁶ are defined as in claim
 1. 8. The compound of claim 7 whereineach of R¹ to R⁶ is independently H or a noninterfering substituentwhich is alkyl (C₁₋₁₀), alkenyl (C₂₋₁₀), alkynyl (C₂₋₁₀), aryl(“C”₅₋₁₂), arylalkyl, arylalkenyl, or arylalkynyl, each of which mayoptionally contain one or more heteroatoms selected from O, S, and N andeach of which may further be substituted; or optionally substitutedforms of acyl, arylacyl, alkyl-alkenyl-, alkynyl- or arylsulfonyl andforms thereof which contain heteroatoms in the alkyl, alkenyl, alkynylor aryl moieties; or which is OR, SR, NR₂, COOR, CONR₂, where R is H oroptionally substituted alkyl, alkenyl, alkynyl or aryl as defined above;and wherein, when the substituted atom is C, the noninterferingsubstituent may be halo, OOCR, NROCR, where an R is H or a substituentset forth above, or may be =O.
 9. The compound of claim 1 wherein saidcompound is of the formula

or the salts or pro-drug forms thereof; and including any stereoisomericforms thereof; wherein R¹—R are defined as in claim 1, and n4 is 2-6.10. The compound of claim 9 wherein each of R¹ to R⁶ is independently Hor a noninterfering substituent which is alkyl (C₁₋₁₀), alkenyl (C₂₋₁₀),alkynyl (C₂₋₁₀), aryl (“C”₅₋₁₂), arylalkyl, arylalkenyl, or arylalkynyl,each of which may optionally contain one or more heteroatoms selectedfrom O, S, and N and each of which may further be substituted; oroptionally substituted forms of acyl, arylacyl, alkyl-alkenyl-, alkynyl-or arylsulfonyl and forms thereof which contain heteroatoms in thealkyl, alkenyl, alkynyl or aryl moieties; or which is OR, SR, NR₂, COOR,CONR₂, where R is H or optionally substituted alkyl, alkenyl, alkynyl oraryl as defined above; and wherein, when the substituted atom is C, thenoninterfering substituent may be halo, OOCR, NROCR, where an R is H ora substituent set forth above, or may be =O.
 11. The compound of claim 1wherein each R¹ is independently H, halo, alkyl, alkoxy, or CF₃.
 12. Thecompound of claim 1 wherein each R² is independently H or alkyl.
 13. Thecompound of claim 1 wherein R³ is H, alkyl, alkenyl, arylalkyl, or aryl.14. The compound of claim 1 wherein each R⁴ is H or alkyl or wherein twoR⁴ together form an aromatic ring.
 15. The compound of claim 1 whereineach R⁵ is independently H, alkyl, or alkenyl, wherein said alkyl oralkenyl may optionally be substituted.
 16. The compound of claim 15wherein said alkyl or alkenyl substituents on a single carbon or onnonadjacent or adjacent carbons form a saturated or unsaturated ring,wherein said ring cannot be aromatic.
 17. The compound of claim 1wherein one R⁵ is an oxime, an alkylated oxime, alkylated hydroxylamine,hydroxylamine or halo.
 18. The compound of claim 1 wherein each R⁶ isindependently H, or optionally heteroatom-containing arylalkyl,arylsulfonyl, or comprises a guanidyl, carbonyl, or carbamino group. 19.The compound of claim 1 wherein two R⁶ form a saturated, unsaturated oraromatic ring, wherein said ring may optionally contain one or moreheteroatoms (N, S or O).
 20. The compound of claim 1 wherein one R⁵ andone R⁶ form a saturated or unsaturated or aromatic ring, which ring mayoptionally contain an additional heteroatom.
 21. A pharmaceuticalcomposition which comprises at least one compound of claim 1, inadmixture with a pharmaceutically acceptable excipient.
 22. Thecomposition of claim 21 which comprises at least one additionalbiologically active agent.
 23. A method to modulate the CXCR4 and/orCCR5 receptor, which method comprises contacting cells displaying saidreceptor(s) with an amount of the compound of claim 1 effective tomodulate said receptor(s).
 24. A method to treat conditionscharacterized by inappropriate activity of the CXCR4 and/or CCR5receptor, which method comprises administering to a subject in need ofsuch treatment an effective amount of the compound of claim 1 or apharmaceutical composition thereof.
 25. A method to treat an undesiredcondition in a human or animal subject which method comprisesadministering to a subject in need of such treatment an effective amountof the compound of claim 1 or a pharmaceutical composition thereof by aclinically acceptable route of administration according to a clinicallyeffective regime.
 26. The method of claim 25, wherein said condition ismodulated by a chemokine receptor.
 27. The method of claim 26, whereinthe chemokine receptor is the CXCR4 or the CCR5 receptor.
 28. The methodof claim 25, wherein said condition is characterized by angiogenesis.29. The method of claim 26, wherein said condition comprises tumors. 30.The method of claim 29, wherein said tumors are of brain, breast,prostate, lung or haematopoetic tissues.
 31. The method of claim 26,wherein said condition is HIV infection.
 32. The method of claim 26,wherein said condition is rheumatoid arthritis.
 33. The method of claim26, wherein said condition is an inflammatory or allergic disease. 34.The method of claim 33, wherein said condition is asthma.
 35. The methodof claim 26, wherein said condition is allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic pneumonias, delayed-type hypersensitivity, interstitiallung disease; systemic anaphylaxis or hypersensitivity responses, drugallergies, insect sting allergies; autoimmune diseases, such asrheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus,myastenia gravis, juvenile onset diabetes; glomerulonephritis,autoimmune throiditis, graft rejection, including allograft rejection orgraft-versus-host disease; inflammatory bowel diseases, such as Crohn'sdisease and ulcerative colitis; spondyloarthropathies; scleroderma;psoriasis; dermatitis, eczema, atopic dermatitis, allergic contactdermatitis, urticaria; vasculitis; eosinphilic myotis, eosiniphilicfasciitis; or cancers.
 36. The method of claim 26, wherein the conditionis associated with immunosuppression.
 37. The method of claim 36,wherein said subject is undergoing chemotherapy, radiation therapy,wound healing, bum treatment, or therapy for autoimmune disease.
 38. Thecompound of claim 1 which is a compound selected from the groupconsisting of compounds 1-171.